Diagnosis, treatment, and follow-up of medullary thyroid carcinoma: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism

Ana Luiza Maia Debora R. Siqueira Marco A. V. Kulcsar Alfio J. Tincani Glaucia M. F. S. Mazeto Lea M. Z. Maciel About the authors

Abstracts

Introdução

O carcinoma medular de tireoide (CMT) origina-se das células parafoliculares da tireoide e corresponde a 3-4% das neoplasias malignas da glândula. Aproximadamente 25% dos casos de CMT são hereditários e decorrentes de mutações ativadoras no proto-oncogene RET (REarranged during Transfection). O CMT é uma neoplasia de curso indolente, com taxas de sobrevida dependentes do estádio tumoral ao diagnóstico. Este artigo descreve diretrizes baseadas em evidências clínicas para o diagnóstico, tratamento e seguimento do CMT.

Objetivo

O presente consenso, elaborado por especialistas brasileiros e patrocinado pelo Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia, visa abordar o diagnóstico, tratamento e seguimento dos pacientes com CMT, de acordo com as evidências mais recentes da literatura. Materiais e métodos: Após estruturação das questões clínicas, foi realizada busca das evidências disponíveis na literatura, inicialmente na base de dados do MedLine-PubMed e posteriormente nas bases Embase e SciELO – Lilacs. A força das evidências, avaliada pelo sistema de classificação de Oxford, foi estabelecida a partir do desenho de estudo utilizado, considerando-se a melhor evidência disponível para cada questão.

Resultados

Foram definidas 11 questões sobre o diagnóstico, 8 sobre o tratamento cirúrgico e 13 questões abordando o seguimento do CMT, totalizando 32 recomendações. Como um todo, o artigo aborda o diagnóstico clínico e molecular, o tratamento cirúrgico inicial, o manejo pós-operatório e as opções terapêuticas para a doença metastática.

Conclusões

O diagnóstico de CMT deve ser suspeitado na presença de nódulo tireoidiano e história familiar de CMT e/ou associação com feocromocitoma, hiperparatireoidismo e/ou fenótipo sindrômico característico, como ganglioneuromatose e habitus marfanoides. A punção aspirativa por agulha fina do nódulo, a dosagem de calcitonina sérica e o exame anatomopatológico podem contribuir na confirmação do diagnóstico. A cirurgia é o único tratamento que oferece a possibilidade de cura. As opções de tratamento da doença metastática ainda são limitadas e restritas ao controle da doença. Uma avaliação pós-cirúrgica criteriosa para a identificação de doença residual ou recorrente é fundamental para definir o seguimento e a conduta terapêutica subsequente.

Carcinoma medular de tireoide; NEM 2A; NEM 2B; proto-oncogene RET; diagnóstico; tratamento; seguimento


Introduction

Medullary thyroid carcinoma (MTC) originates in the thyroid parafollicular cells and represents 3-4% of the malignant neoplasms that affect this gland. Approximately 25% of these cases are hereditary due to activating mutations in the REarranged during Transfection (RET) proto-oncogene. The course of MTC is indolent, and survival rates depend on the tumor stage at diagnosis. The present article describes clinical evidence-based guidelines for the diagnosis, treatment, and follow-up of MTC.

Objective

The aim of the consensus described herein, which was elaborated by Brazilian experts and sponsored by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism, was to discuss the diagnosis, treatment, and follow-up of individuals with MTC in accordance with the latest evidence reported in the literature. Materials and methods: After clinical questions were elaborated, the available literature was initially surveyed for evidence in the MedLine-PubMed database, followed by the Embase and Scientific Electronic Library Online/Latin American and Caribbean Health Science Literature (SciELO/Lilacs) databases. The strength of evidence was assessed according to the Oxford classification of evidence levels, which is based on study design, and the best evidence available for each question was selected.

Results

Eleven questions corresponded to MTC diagnosis, 8 corresponded to its surgical treatment, and 13 corresponded to follow-up, for a total of 32 recommendations. The present article discusses the clinical and molecular diagnosis, initial surgical treatment, and postoperative management of MTC, as well as the therapeutic options for metastatic disease.

Conclusions

7 Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab. 2005;90:2029-34.

Medullary thyroid carcinoma; MEN 2A; MEN 2B; RET proto-oncogene; diagnosis; treatment; follow-up


INTRODUCTION

Medullary thyroid carcinoma (MTC) originates in the thyroid parafollicular or C cells and represents 3-4% of the malignant neoplasms that affect this gland (1 Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006;295:2164-7.) (A). Overall, 10,590 new cases of thyroid cancer were estimated among Brazilian women in 2012 (National Cancer Institute/Instituto Nacional do Câncer [Inca]; www.inca.gov.br/estimativa/2012). Assuming that the percentage of MTC is similar to that reported in other countries, about 430 new cases of MTC would be diagnosed each year.

MTC can be sporadic or hereditary (20-25%). The familial form is part of a genetic syndrome known as multiple endocrine neoplasia type 2 (MEN 2 Punales MK, Rocha AP, Gross JL, Maia AL. Medullary thyroid carcinoma: clinical and oncological features and treatment. Arq Bras Endocrinol Metabol. 2004;48:137-46.). The most common form of this syndrome is MEN 2A, which is characterized by MTC (95%), pheochromocytoma (50%), and hyperparathyroidism (20%), while MEN 2B includes MTC (90%), pheochromocytoma (45%), ganglioneuromatosis (100%), Marfanoid habitus (65%), and eye abnormalities (e.g., thickened corneal nerves, conjunctivitis sicca, and an inability to cry tears). Familial MTC (FMTC) is defined by the presence of MTC alone, and its diagnosis is based on the absence of pheochromocytoma or hyperparathyroidism in 2 or more family generations or the presence of mutations classically associated with FMTC (2 Punales MK, Rocha AP, Gross JL, Maia AL. Medullary thyroid carcinoma: clinical and oncological features and treatment. Arq Bras Endocrinol Metabol. 2004;48:137-46.,3 Wells SA Jr, Pacini F, Robinson BG, Santoro M. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013;98:3149-64.) (D). Activating mutations in the REarranged during Transfection (RET) proto-oncogene are the cause of the hereditary disease form, and therefore molecular diagnosis is of paramount importance in MTC management (4 Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, et al. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet. 1994;3:237-41.) (A). Approximately 50% of sporadic MTC cases exhibit somatic mutations in the RET gene (4 Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, et al. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet. 1994;3:237-41.,5 Siqueira DR, Romitti M, da Rocha AP, Ceolin L, Meotti C, Estivalet A, et al. The RET polymorphic allele S836S is associated with early metastatic disease in patients with hereditary or sporadic medullary thyroid carcinoma. Endocr Relat Cancer. 2010;17:953-63.) (A/B).

Calcitonin is a specific biomarker with a high sensitivity for MTC diagnosis. Neoplastic C cells also produce the carcinoembryonic antigen (CEA), which can be used as a prognostic marker during the follow-up of individuals with MTC (6 Cohen R, Campos JM, Salaun C, Heshmati HM, Kraimps JL, Proye C, et al. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d’Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab. 2000;85:919-22.,7 Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab. 2005;90:2029-34.) (B). Sporadic MTC is an indolent and usually solitary tumor, whereas the hereditary form is usually multicentric. Diagnosis of the sporadic form is usually established late in life (approximately the fifth or sixth decade). Neck lymph node metastases are detected in approximately 50% of cases at the time of diagnosis, while distant metastases occur in 20% of cases (8 Moley JF, DeBenedetti MK. Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection. Ann Surg. 1999;229:880-7.

Scollo C, Baudin E, Travagli JP, Caillou B, Bellon N, Leboulleux S, et al. Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2003;88:2070-5.

10  Giraudet AL, Vanel D, Leboulleux S, Auperin A, Dromain C, Chami L, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 2007;92:4185-90.
-1111  Girelli ME, Nacamulli D, Pelizzo MR, De Vido D, Mian C, Piccolo M, et al. Medullary thyroid carcinoma: clinical features and long-term follow-up of seventy-eight patients treated between 1969 and 1986. Thyroid. 1998;8:517-23.) (B). Early surgical intervention is the only curative therapeutic approach (1111  Girelli ME, Nacamulli D, Pelizzo MR, De Vido D, Mian C, Piccolo M, et al. Medullary thyroid carcinoma: clinical features and long-term follow-up of seventy-eight patients treated between 1969 and 1986. Thyroid. 1998;8:517-23.) (B). The 10-year survival rate of patients with diseases that only affect the thyroid is 95%, while that in individuals with distant metastases varies from 15-40% (1212  Roman S, Lin R, Sosa JA. Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer. 2006;107:2134-42.) (B).

The recommendations described below resulted from the efforts of the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism to formulate evidence-based clinical guidelines for the care of individuals with MTC. Our main goal is to assist clinicians with the selection of the best strategies for patient management according to the characteristics of the Brazilian health system.

MATERIALS AND METHODS

The present consensus complies with the strategic policy of the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism for the development of national consensuses for the main diseases of the thyroid gland that are specifically formulated for the Brazilian population, while considering the actual situation of the national health system. The Program Guidelines, which were elaborated by the Brazilian Medical Association (Associação Médica Brasileira [AMB]) and the Federal Council of Medicine (Conselho Federal de Medicina [CFM]), served as a model for the present recommendations. The authors were selected according to their academic and scientific activities and clinical experiences with the management of these diseases. The clinical questions most relevant to the clinical practice were then formulated. A search for relevant articles was performed in the databases MedLine-PubMed, Embase, and Scientific Electronic Library Online/Latin American and Caribbean Health Science Literature (SciELO-Lilacs). The grade of recommendation or strength of evidence (Table 1) of the studies was established according to the Oxford classification (1313  Levels of Evidence and Grades of Recommendations – Oxford Centre for Evidence-Based Medicine. Disponível em: http://www.cebm.net/index.aspx?o=1025. Acesso em: 1 Out, 2014.
http://www.cebm.net/index.aspx?o=1025...
) (D), which is based on the study design used, while considering the best available evidence and the Brazilian experience. This method was also used in the AMB/CFM Program Guidelines, to which the Brazilian medical community and academic milieu grew accustomed.

Table 1
Definition of the grades of recommendation and strength of evidence according to the Oxford classification (adapted from reference 1313  Levels of Evidence and Grades of Recommendations – Oxford Centre for Evidence-Based Medicine. Disponível em: http://www.cebm.net/index.aspx?o=1025. Acesso em: 1 Out, 2014.
http://www.cebm.net/index.aspx?o=1025...
) (D)

The search of the MedLine-PubMed, Embase, and SciELO databases allowed the identification of studies that focused on several features related to the diagnosis, treatment, and follow-up of MTC. The recommendations presented herein summarize the relevant aspects of each clinical question and are categorized as a function of the evidential strength on which they are based, as described in table 1.

PART I: MTC: DIAGNOSIS

1. When should we suspect MTC?

The most common clinical presentation of MTC is the appearance of a single thyroid nodule. Thyroid nodules might also eventually appear within the context of a multinodular goiter or might represent an incidental finding in imaging exams of the neck (1414  Rosário PW, Ward LS, Carvalho GA, Graf H, Maciel RM, Maciel LM, et al. Thyroid nodules and differentiated thyroid cancer: update on the Brazilian consensus. Arq Bras Endocrinol Metabol. 2013;57:240-64.) (D). Neck lymph node enlargement is present in 50% of these cases (8 Moley JF, DeBenedetti MK. Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection. Ann Surg. 1999;229:880-7.,9 Scollo C, Baudin E, Travagli JP, Caillou B, Bellon N, Leboulleux S, et al. Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2003;88:2070-5.) (B). Although the detection of fast-growing or hardened lymph nodes or their fixation to adjacent structures is suggestive of malignancy, this does not specifically indicate MTC. The presence of associated endocrine neoplasms (pheochromocytoma, hyperparathyroidism), cutaneous lichen amyloidosis on the interscapular region, ganglioneuromas, typical facies, or a history of thyroid cancer and/or of RET mutations in first-degree relatives might be suggestive of hereditary MTC (2 Punales MK, Rocha AP, Gross JL, Maia AL. Medullary thyroid carcinoma: clinical and oncological features and treatment. Arq Bras Endocrinol Metabol. 2004;48:137-46.

Wells SA Jr, Pacini F, Robinson BG, Santoro M. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013;98:3149-64.
-4 Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, et al. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet. 1994;3:237-41.,1515  Steiner AL, Goodman AD, Powers SR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing’s disease: multiple endocrine neoplasia, type 2. Medicine. 1968;47:371-409.) (D/D/B/C). In a small fraction of patients, MTC exhibits systemic manifestations such as diarrhea, flushing, Cushing’s syndrome due to the ectopic secretion of adrenocorticotropic hormone (ACTH), or fractures secondary to bone metastases (2 Punales MK, Rocha AP, Gross JL, Maia AL. Medullary thyroid carcinoma: clinical and oncological features and treatment. Arq Bras Endocrinol Metabol. 2004;48:137-46.,3 Wells SA Jr, Pacini F, Robinson BG, Santoro M. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013;98:3149-64.,1515  Steiner AL, Goodman AD, Powers SR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing’s disease: multiple endocrine neoplasia, type 2. Medicine. 1968;47:371-409.) (D/D/C).

There are no specific clinical findings that permit a firm diagnosis of MTC. For this reason, if CMT is suspected, the physician should order diagnostic tests, including fine-needle aspiration biopsy (FNAB) and serum calcitonin measurements.

Recommendation 1

A thyroid nodule is the most common clinical manifestation of MTC. MTC must be specifically suspected in individuals with family history of thyroid cancer, RET mutations, and/or associations with pheochromocytoma, hyperparathyroidism, cutaneous lichen amyloidosis and/or typical findings upon physical examination such as Marfanoid habitus and mucosal neuromas (Recommendation B).

2. What is the role of fine-needle aspiration biopsy (FNAB) in the diagnosis of MTC?

FNAB is among the most important tools for the diagnostic assessment of thyroid nodules. The characteristic cytological findings in MTC include the presence of predominantly isolated cells or cells arranged in isolated cohesive groups, with a round-to-oval, polyhedral, or fusiform shape, and the predominance of 3-dimensional arrangements; abundant or scarce cytoplasm that usually contains acidophil granulation; 2 or more typically round nuclei of variable size (usually present in alterations associated with endocrine disorders) and eccentric position; and the presence of amyloid, which usually appears as clumps of amorphous matter detected by Congo red staining. Further cytological findings include the presence of fusiform cells and cytoplasmic (comet-like) projections (1616  Papaparaskeva K, Nagel H, Droese M. Cytologic diagnosis of medullary carcinoma of the thyroid gland. Diagn Cytopathol. 2000;22:351-8.) (B).

The sensitivity of FNAB for diagnosing MTC in a thyroid nodule varies from 46.1-63% (1717  Essig GF Jr, Porter K, Schneider D, Debora A, Lindsey SC, Busonero G, et al. Fine needle aspiration and medullary thyroid carcinoma: the risk of inadequate preoperative evaluation and initial surgery when relying upon FNAB cytology alone. Endocr Pract. 2013;19:920-7.

18  Bugalho MJ, Santos JR, Sobrinho L. Preoperative diagnosis of medullary thyroid carcinoma: fine needle aspiration cytology as compared with serum calcitonin measurement. J Surg Oncol. 2005;91:56-60.
-1919  Chang TC, Wu SL, Hsiao YL. Medullary thyroid carcinoma: pitfalls in diagnosis by fine needle aspiration cytology and relationship of cytomorphology to RET proto-oncogene mutations. Acta Cytol. 2005;49:477-82.) (B). Although non-diagnostic, the FNAB findings in MTC are indicative of surgery in 99% of cases (1717  Essig GF Jr, Porter K, Schneider D, Debora A, Lindsey SC, Busonero G, et al. Fine needle aspiration and medullary thyroid carcinoma: the risk of inadequate preoperative evaluation and initial surgery when relying upon FNAB cytology alone. Endocr Pract. 2013;19:920-7.

18  Bugalho MJ, Santos JR, Sobrinho L. Preoperative diagnosis of medullary thyroid carcinoma: fine needle aspiration cytology as compared with serum calcitonin measurement. J Surg Oncol. 2005;91:56-60.
-1919  Chang TC, Wu SL, Hsiao YL. Medullary thyroid carcinoma: pitfalls in diagnosis by fine needle aspiration cytology and relationship of cytomorphology to RET proto-oncogene mutations. Acta Cytol. 2005;49:477-82.) (B). Approximately 82% of MTC cases are correctly identified by FNAB, while 9% are false-negative results (1818  Bugalho MJ, Santos JR, Sobrinho L. Preoperative diagnosis of medullary thyroid carcinoma: fine needle aspiration cytology as compared with serum calcitonin measurement. J Surg Oncol. 2005;91:56-60.,1919  Chang TC, Wu SL, Hsiao YL. Medullary thyroid carcinoma: pitfalls in diagnosis by fine needle aspiration cytology and relationship of cytomorphology to RET proto-oncogene mutations. Acta Cytol. 2005;49:477-82.) (B).

The most frequent reasons for FNAB failure are inadequate sampling and multinodular goiters (because the malignant nodule might not be selected for assessment) (2020  Shah SS, Faquin WC, Izquierdo R, Khurana KK. FNA of misclassified primary malignant neoplasms of the thyroid: impact on clinical management. Cytojournal. 2009;6:1.) (B). Additionally, differential diagnosis between MTC and other malignant thyroid neoplasms (particularly follicular lesions, Bethesda category III or IV) might be difficult because the cytological findings can be similar (2020  Shah SS, Faquin WC, Izquierdo R, Khurana KK. FNA of misclassified primary malignant neoplasms of the thyroid: impact on clinical management. Cytojournal. 2009;6:1.,2121  Forrest CH, Frost FA, de Boer WB, Spagnolo DV, Whitaker D, Sterrett BF. Medullary carcinoma of the thyroid: accuracy of diagnosis of fine-needle aspiration cytology. Cancer. 1998;84:295-302.) (B).

The measurement of calcitonin in the washout fluid has been recommended to improve the diagnostic sensitivity of FNAB for MTC (2222  Boi F, Maurelli I, Pinna G, Atzeni F, Piga M, Lai ML, et al. Calcitonin measurement in wash-out fluid from fine needle aspiration of neck masses in patients with primary and metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab. 2007;92:2115-8.,2323  Siqueira D, Rocha AP, Punales MK, Maia AL. Identification of occult metastases of medullary thyroid carcinoma by calcitonin measurement in washout fluid from fine needle aspiration of cervical lymph node. Arq Bras Endocrinol Metabol. 2009;53:479-81.) (B/C). In a recent retrospective study, the cytology detected MTC in 21/37 lesions with 56.8% sensitivity whereas the measurement of calcitonin in the washout fluid showed sensitivity and specificity rates of 100% using a cutoff of 36 pg/mL (2424  Trimboli P, Cremonini N, Ceriani L, Saggiorato E, Guidobaldi L, Romanelli F, et al. Calcitonin measurement in aspiration needle washout fluids has higher sensitivity than cytology in detecting medullary thyroid cancer: a retrospective multicentre study. Clin Endocrinol. 2014;80:135-40.) (B).

The failure to diagnose MTC in a cytological examination might negatively impact the therapeutic management of patients (2020  Shah SS, Faquin WC, Izquierdo R, Khurana KK. FNA of misclassified primary malignant neoplasms of the thyroid: impact on clinical management. Cytojournal. 2009;6:1.) (B). Immunochemical staining for calcitonin might be useful in doubtful cases (2525  Takeichi N, Ito H, Okamoto H, Matsuyama T, Tahara E, Dohi K. The significance of immunochemically staining calcitonin and CEA in fine-needle aspiration biopsy materials from medullary carcinoma of the thyroid. Jpn J Surg. 1989;19:674-8.) (C). Other methods that might facilitate the diagnosis of MTC include scanning electron microscopy and assessments of calcitonin mRNA expression; however, these are not part of the diagnostic routine (2525  Takeichi N, Ito H, Okamoto H, Matsuyama T, Tahara E, Dohi K. The significance of immunochemically staining calcitonin and CEA in fine-needle aspiration biopsy materials from medullary carcinoma of the thyroid. Jpn J Surg. 1989;19:674-8.

26  Takano T, Miyauchi A, Matsuzuka F, Liu G, Higashiyama T, Yokozawa T, et al. Preoperative diagnosis of medullary thyroid carcinoma by RT-PCR using RNA extracted from leftover cells within a needle used for fine needle aspiration biopsy. J Clin Endocrinol Metab. 1999;84:951-5.

27  Nesland JM, Sobrinho-Simoes M, Johannessen JV. Scanning electron microscopy of the human thyroid gland and its disorders. Scanning Microsc. 1987;1:1797-810.
-2828  Chang TC, Lai SM, Wen CY, Hsiao YL, Huang SH. Three-dimensional cytomorphology in fine needle aspiration biopsy of medullary thyroid carcinoma. Acta Cytol. 2001;45:980-4.) (C).

Recommendation 2

FNAB should be included in assessments of thyroid nodules suspected of MTC (Recommendation B). Diagnosis might be facilitated by the use of additional techniques such as calcitonin measurement in the FNAB washout fluid (Recommendation B) and immunocytochemistry (Recommendation C).

3. What is the role of the serum calcitonin measurement in thyroid nodule assessments?

The indication for serum calcitonin measurements in thyroid nodule assessments remains controversial. According to the basal calcitonin levels, the positive predictive values of this test are 8.3%, 25%, and 100% for calcitonin levels of 20-50 pg/mL, 50-100 pg/mL, and > 100 pg/mL, respectively (2929  Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S, et al. Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab. 2007;92:450-5.) (A). According to some authors, the basal calcitonin levels should be measured first, followed by a pentagastrin stimulation test if the basal calcitonin levels exceed 10 pg/mL. The risk of MTC is greater than 50% if the pentagastrin-stimulated calcitonin values > 100 pg/mL (3030  Karges W, Dralle H, Raue F, Mann K, Reiners C, Grussendorf M, et al. Calcitonin measurement to detect medullary thyroid carcinoma in nodular goiter: German evidence-based consensus recommendation. Exp Clin Endocrinol Diabetes. 2004;112:52-8.) (D). In comparison with the ultrasensitive calcitonin, the pentagastrin test still shows better diagnostic capability (3131  Pina G, Dubois S, Murat A, Berger N, Niccoli P, Peix JL, et al Groupe des Tumeurs Endocrines. Is basal ultrasensitive measurement of calcitonin capable of substituting for the pentagastrin-stimulation test? Clin Endocrinol (Oxf). 2013;78:358-64.) (A). However, the pentagastrin stimulation test is not available in Brazil. The calcium stimulation test can be used as an alternative (3232  Colombo C, Verga U, Mian C, Ferrero S, Perrino M, Vicentini L, et al. Comparison of calcium and pentagastrin tests for the diagnosis and follow-up of medullary thyroid cancer. J Clin Endocrinol Metab. 2012;97:905-13.) (B). Nevertheless, recent studies have shown that with the improved sensitivity of the new assays, both basal and stimulated calcitonin have similar accuracy, which reduces the relevance of the stimulation tests in multiple conditions (3333  Mian C, Perrino M, Colombo C, Cavedon E, Pennelli G, Ferrero S, et al. Refining calcium test for the diagnosis of medullary thyroid cancer: cutoffs, procedures, and safety. J Clin Endocrinol Metab. 2014;99:1656-64.) (B).

Calcitonin is a sensitive and specific biomarker for the diagnosis of C cell hyperplasia and/or MTC. Increased calcitonin levels might also be present in other diseases such as chronic kidney failure, hyperparathyroidism, neuroendocrine neoplasms, lung and prostate tumors and autoimmune thyroiditis (3434  Tashijan AH Jr, Howland BG, Melvin KE, Hill CS Jr. Immunoassay of human calcitonin. N Engl J Med. 1970;283:890-5.,3535  Karanikas G, Moameni A, Poetzi C, Zettinig G, Kaserer K, Bieglmayer C, et al. Frequency and relevance of elevated calcitonin levels in patients with neoplastic and nonneoplastic thyroid disease and in healthy subjects. J Clin Endocrinol Metab. 2004;89:515-9.) (D/B), which are considered classic causes of false-positive results. Presence of heterophile antibodies (human antibodies with broad reactivity with antibodies of other species) can also interfere in dosage, causing falsely elevated values (or, less frequently, false-positive results) (3636  Preissner CM, Dodge LA, O’Kane DJ, Singh RJ, Grebe SK. Prevalence of heterophilic antibody interference in eight automated tumor marker immunoassays. Clin Chem. 2005; 51:208-10.) (B). Of note, recent study conducted in Brazil found no changes in the serum calcitonin levels of individuals with Hashimoto’s thyroiditis (3737  Rosario PW, Calsolari MR. influence of chronic autoimmune thyroiditis and papillary thyroid cancer on serum calcitonin levels. Thyroid. 2013;23:671-4.) (B). False-negative results might be due to the hook effect and, less often, to non-calcitonin-secreting MTC (3838  Leboeuf R, Langlois MF, Martin M, Ahnadi CE, Fink GD. “Hook effect” in calcitonin immunoradiometric assay in patients with metastatic medullary thyroid carcinoma: case report and review of the literature. J Clin Endocrinol Metab. 2006;91:361-4.,3939  Dora JM, Canalli MH, Capp C, Punales MK, Vieira JG, Maia AL. Normal perioperative serum calcitonin levels in patients with advanced medullary thyroid carcinoma: case report and review of the literature. Thyroid. 2008;18:895-9.) (C).

Compared with FNAB, the sensitivity of the calcitonin measurement for preoperative diagnosis of MTC is higher (approximately 100% sensitivity and 95% specificity) (1818  Bugalho MJ, Santos JR, Sobrinho L. Preoperative diagnosis of medullary thyroid carcinoma: fine needle aspiration cytology as compared with serum calcitonin measurement. J Surg Oncol. 2005;91:56-60.,4040  Hasselgren M, Hegedus L, Godballe C, Bonnema SJ. Benefit of measuring basal serum calcitonin to detect medullary thyroid carcinoma in a Danish population with a high prevalence of thyroid nodules. Head Neck. 2010;32:612-8.,4141  Papi G, Corsello SM, Cioni K, Pizzini AM, Corrado S, Carapezzi C, et al. Value of routine measurement of serum calcitonin concentrations in patients with nodular thyroid disease: a multicenter study. J Endocrinol Invest. 2006;29:427-37.) (B). Individuals with MTC that was diagnosed from a calcitonin measurement during the investigation of thyroid nodules exhibit better postoperative outcomes than do those diagnosed by FNAB, with 10-year survival rates of 86.8% and 43.7%, respectively (4242  Elisei R, Bottici V, Luchetti F, Di Coscio G, Romei C, Grasso L, et al. Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. J Clin Endocrinol Metab. 2004;89:163-8.) (B).

In North America, studies of cost-effectiveness obtained results favorable to the inclusion of calcitonin measurements in initial thyroid nodule assessments (4343  Borget I, De Pouvourville G, Schlumberger M. Editorial: calcitonin determination in patients with nodular thyroid disease. J Clin Endocrinol Metab. 2007;92:425-7.,4444  Cheung K, Roman SA, Wang TS, Walker HD, Sosa JA. Calcitonin measurement in the evaluation of thyroid nodules in the United States: a cost-effectiveness and decision analysis. J Clin Endocrinol Metab. 2008;93:2173-80.) (D/B). Those data lend further support to the usefulness of calcitonin measurements in nodule investigations. Those results notwithstanding, the low prevalence of MTC (0.42-2.85%), the test costs, and problems with the standardization of the cutoff points cast doubts on the actual benefit provided by calcitonin measurements (4242  Elisei R, Bottici V, Luchetti F, Di Coscio G, Romei C, Grasso L, et al. Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. J Clin Endocrinol Metab. 2004;89:163-8.,4545  Rieu M, Lame MC, Richard A, Lissak B, Sambort B, Vuong-Ngoc P, et al. Prevalence of sporadic medullary thyroid carcinoma: the importance of routine measurement of serum calcitonin in the diagnostic evaluation of thyroid nodules. Clin Endocrinol (Oxf). 1995;42:453-60.

46  Ozgen AG, Hamulu F, Bayraktar F, Yilmaz C, Tuzun M, Yetkin E, et al. Evaluation of routine basal serum calcitonin measurement for early diagnosis of medullary thyroid carcinoma in seven hundred seventy-three patients with nodular goiter. Thyroid. 1999;9:579-82.
-4747  Hahm JR, Lee MS, Min YK, Lee MK, Kim KW, Nam SJ, et al. Routine measurement of serum calcitonin is useful for early detection of medullary thyroid carcinoma in patients with nodular thyroid diseases. Thyroid. 2001;11:73-80.) (B). Additionally, the reproducibility of those results in our milieu is doubtful. For those reasons, the Brazilian consensus for thyroid nodules does not recommend the measurement of serum calcitonin in the initial nodule assessment (1414  Rosário PW, Ward LS, Carvalho GA, Graf H, Maciel RM, Maciel LM, et al. Thyroid nodules and differentiated thyroid cancer: update on the Brazilian consensus. Arq Bras Endocrinol Metabol. 2013;57:240-64.) (B). However, measurement of calcitonin in the FNAB washout fluid may be useful in nodules with undetermined results (Bethesda category III/IV), considering the difficulties of FNAB to differentiate MTC from other thyroid malignancies (particularly follicular lesions) (2424  Trimboli P, Cremonini N, Ceriani L, Saggiorato E, Guidobaldi L, Romanelli F, et al. Calcitonin measurement in aspiration needle washout fluids has higher sensitivity than cytology in detecting medullary thyroid cancer: a retrospective multicentre study. Clin Endocrinol. 2014;80:135-40.) (B).

The prevalence of MTC in individuals with multinodular goiters varies from 0-3.1% (4848  Ahmed SR, Ball DW. Clinical review: Incidentally discovered medullary thyroid cancer: diagnostic strategies and treatment. J Clin Endocrinol Metab. 2011;96:1237-45.) (A). It is worth bearing in mind that FNAB might yield false-negative results in cases of multinodular goiters because not all nodules can be feasibly assessed (4949  Elisei R. Routine serum calcitonin measurement in the evaluation of thyroid nodules. Best Pract Res Clin Endocrinol Metab. 2008;22:941-53.) (D). Additionally, small MTC foci might not be identified with thyroid ultrasound (US). For all those reasons, the serum calcitonin measurement might be useful for detecting MTC in cases of multinodular goiter (5050  Vierhapper H, Raber W, Bieglmayer C, Kaserer K, Weinhausl A, Niederle B. Routine measurement of plasma calcitonin in nodular thyroid diseases. J Clin Endocrinol Metab. 1997;82:1589-93.,5151  Pacini F, Fontanelli M, Fugazzola L, Elisei R, Romei C, Di Coscio G, et al. Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab. 1994;78:826-9.) (A).

Recommendation 3

MTC screening via a serum calcitonin measurement in individuals with thyroid nodules remains controversial. Because of problems with reference value standardization and its doubtful cost-effectiveness, the measurement of serum calcitonin is not indicated in the routine investigation of thyroid nodules (Recommendation B).

4. What are the meanings of the serum levels of tumor markers for the initial diagnosis of MTC?

MTC secretes a variety of products, including calcitonin, CEA, amyloid, somatostatin, ACTH, vasoactive intestinal peptide (VIP), and serotonin, among others (5252  Said SI. Evidence for secretion of vasoactive intestinal peptide by tumours of pancreas, adrenal medulla, thyroid and lung: support for the unifying APUD concept. Clin Endocrinol (Oxf). 1976;5 Suppl:201S-4S.,5353  Holm R, Sobrinho-Simoes M, Nesland JM, Gould VE, Johannessen JV. Medullary carcinoma of the thyroid gland: an immunocytochemical study. Ultrastruct Pathol. 1985;8:25-41.) (B). Calcitonin is the most important biomarker and is used in the diagnosis, surgical planning, postoperative management, and prognosis of individuals with MTC (5454  Pacini F, Castagna MG, Cipri C, Schlumberger M. Medullary thyroid carcinoma. Clin Oncol (R Coll Radiol). 2010;22:475-85.) (D).

In individuals with MTC, the preoperative calcitonin levels correlate with the tumor size and the presence of metastases (6 Cohen R, Campos JM, Salaun C, Heshmati HM, Kraimps JL, Proye C, et al. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d’Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab. 2000;85:919-22.,7 Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab. 2005;90:2029-34.) (B). Calcitonin levels < 100 pg/mL are associated with an average tumor diameter of 3 mm, while levels > 1,000 pg/mL are associated with an average tumor diameter of 2.5 cm. Neck lymph node metastases might be present with basal calcitonin levels of 10-40 pg/mL, while metastatic disease should be suspected at levels of 150-400 pg/mL. The presence of lymph node metastases or calcitonin levels > 400 pg/mL indicate the need to identify distant metastases (6 Cohen R, Campos JM, Salaun C, Heshmati HM, Kraimps JL, Proye C, et al. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d’Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab. 2000;85:919-22.,7 Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab. 2005;90:2029-34.) (B).

Additionally, the serum CEA levels might be used for the risk stratification of individuals with MTC. CEA levels > 30 ng/mL are suggestive of lymph node metastases in the ipsilateral central and lateral neck compartments, while levels > 100 ng/mL correlate with contralateral lymph node metastases and distant metastases. Values > 30 ng/mL were found to correlate with low cure rates (5555  Machens A, Ukkat J, Hauptmann S, Dralle H. Abnormal carcinoembryonic antigen levels and medullary thyroid cancer progression: a multivariate analysis. Arch Surg. 2007;142:289-93.) (B).

The preoperative serum calcitonin levels seem to correlate more strongly with extensions of MTC, as compared to the neck US findings. Basal calcitonin levels of 20, 50, 200, and 500 pg/mL exhibited correlations with metastases in the lymph nodes of the ipsilateral, lateral, and central compartments, contralateral central compartment, contralateral lateral compartment, and superior mediastinum, respectively (5656  Machens A, Dralle H. Biomarker-based risk stratification for previously untreated medullary thyroid cancer. J Clin Endocrinol Metab. 2010;95:2655-63.) (B).

Recommendation 4

Preoperative calcitonin levels correlate with the tumor size and stage and indicate the presence of local and/or distant metastases (Recommendation B). The individuals with suspected MTC and calcitonin levels > 150 ng/mL must be investigated for the presence of locoregional and distant metastases by imaging tests (please see Recommendation 6 Cohen R, Campos JM, Salaun C, Heshmati HM, Kraimps JL, Proye C, et al. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d’Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab. 2000;85:919-22., Flowchart 1) (Recommendation B).

Flowchart 1
. Initial diagnostic approach of medullary thyroid carcinoma.

5. What is the value of neck US for the diagnosis of MTC?

Thyroid US is a relevant part of a thyroid nodule assessment. US allows an accurate assessment of the nodule size and characteristics, as well as the identification of other nodules. Some nodule characteristics evidenced by US correlate with a higher risk of malignancy, including hypoechogenicity, microcalcifications, irregular margins, predominantly central vascularization, and the presence of enlarged neck lymph nodes (5757  Peccin S, de Castsro JA, Furlanetto TW, Furtado AP, Brasil BA, Czepielewski MA. Ultrasonography: is it useful in the diagnosis of cancer in thyroid nodules? J Endocrinol Invest. 2002;25:39-43.

58  Alexander EK, Marqusee E, Orcutt J, Benson CB, Frates MC, Doubilet PM, et al. Thyroid nodule shape and prediction of malignancy. Thyroid. 2004;14:953-8.
-5959  Tomimori EK, Bisi H, Medeiros-Neto G, Camargo RY. [Ultrasonographic evaluation of thyroid nodules: comparison with cytologic and histologic diagnosis]. Arq Bras Endocrinol Metabol. 2004;48:105-13.) (B).

Most individuals with MTC (> 90%) exhibit hypoechoic nodules, intranodular calcifications, and an absence of the halo sign on US; further possible findings include the presence of intranodular (79%) and perinodular (50%) blood flow (6060  Saller B, Moeller L, Gorges R, Janssen OE, Mann K. Role of conventional ultrasound and color Doppler sonography in the diagnosis of medullary thyroid carcinoma. Exp Clin Endocrinol Diabetes. 2002;110:403-7.) (B). Some cases exhibit intranodular bright echogenic foci that correspond to amyloid-surrounded calcium deposits (6161  Gorman B, Charboneau JW, James EM, Reading CC, Wold LE, Grant CS, et al. Medullary thyroid carcinoma: role of high-resolution US. Radiology. 1987;162:147-50.) (B).

Neck US is the most sensitive imaging method for neck metastasis detection (1010  Giraudet AL, Vanel D, Leboulleux S, Auperin A, Dromain C, Chami L, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 2007;92:4185-90.) (B). Approximately 75% of patients with MTC that is clinically detectable by palpation exhibit lymph node metastases (8 Moley JF, DeBenedetti MK. Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection. Ann Surg. 1999;229:880-7.) (B). As the presence of lymph node and/or distant metastases indicates the need for changes in the therapeutic management, US might be considered indispensable for treatment planning. The sensitivity of preoperative neck US is considered as moderate, since 32% and 14% of individuals exhibit false-negative results in the central and ipsilateral areas, respectively (6262  Kouvaraki MA, Shapiro SE, Fornage BD, Edeiken-Monro BS, Sherman SI, Vassilopoulou-Sellin R, et al. Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer. Surgery. 2003;134:946-54.) (B). However, a recent study described higher rates of sensitivity of US in predicting metastasis in the lateral and central neck (93.8% and 30.0%, respectively) (6363  Hwang HS, Orloff LA. Efficacy of preoperative neck ultrasound in the detection of cervical lymph node metastasis from thyroid cancer. Laryngoscope. 2011;121:487-91.) (B). One important limitation of US is that it is operator-dependent, and therefore the results vary as a function of the operator’s experience. This most likely explains why a larger number of neck lymph node metastases are detected with surgical dissection, compared to US. Nevertheless, the sensitivity, specificity, and diagnostic accuracy of US for the preoperative detection of neck metastases are superior to those of computed tomography (CT; 77, 70, and 74% vs. 62, 79, and 68%, respectively) (6464  Ahn JE, Lee JH, Yi JS, Shong YK, Hong SJ, Lee DH, et al. Diagnostic accuracy of CT and ultrasonography for evaluating metastatic cervical lymph nodes in patients with thyroid cancer. World J Surg. 2008;32:1552-8.) (B). Preoperative neck US is a valuable tool in assessing patients with thyroid nodules; it provides useful information predicting cervical lymph node metastasis, especially in the in the lateral neck, and thus defining surgical extension (6363  Hwang HS, Orloff LA. Efficacy of preoperative neck ultrasound in the detection of cervical lymph node metastasis from thyroid cancer. Laryngoscope. 2011;121:487-91.) (B).

Recommendation 5

Neck US is indicated in all individuals with suspected MTC (Recommendation B). In addition to identifying characteristics suggestive of malignancy in the thyroid nodules and allowing the performance of US-guided FNAB, US is the most sensitive test for detecting neck metastases and thus contributes to therapeutic planning (Recommendation B).

6. Which complementary tests should be performed before thyroidectomy in patients with suspected MTC?

The aim of the preoperative assessment of individuals with suspected or confirmed MTC is to establish the extension of thyroid disease and to identify the eventual presence of associated comorbidities such as hyperparathyroidism and/or pheochromocytoma in hereditary cases.

The presence of local and/or distant metastases interferes with surgery planning in individuals with MTC. Neck metastases appear early during the course of MTC (9 Scollo C, Baudin E, Travagli JP, Caillou B, Bellon N, Leboulleux S, et al. Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2003;88:2070-5.,6565  Moley JF, Brother MB, Wells SA, Spengler BA, Biedler JL, Brodeur GM. Low frequency of ras gene mutations in neuroblastomas, pheochromocytomas, and medullary thyroid cancers. Cancer Res. 1991;51:1596-9.) (B). Distant metastases are detected in 7-17% of all cases at the time of diagnosis and frequently appear in multiple sites (lungs, liver, bones, and less often in the brain and skin) (1010  Giraudet AL, Vanel D, Leboulleux S, Auperin A, Dromain C, Chami L, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 2007;92:4185-90.,1111  Girelli ME, Nacamulli D, Pelizzo MR, De Vido D, Mian C, Piccolo M, et al. Medullary thyroid carcinoma: clinical features and long-term follow-up of seventy-eight patients treated between 1969 and 1986. Thyroid. 1998;8:517-23.,6666  Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer. 2000;88:1139-48.,6767  Bergholm U, Adami HO, Bergstrom R, Johansson H, Lundell G, Telenius-Berg M, et al. Clinical characteristics in sporadic and familial medullary thyroid carcinoma. A nationwide study of 249 patients in Sweden from 1959 through 1981. Cancer. 1989;63:1196-204.) (B/B/B/A).

Neck US must be performed in all affected individuals (5656  Machens A, Dralle H. Biomarker-based risk stratification for previously untreated medullary thyroid cancer. J Clin Endocrinol Metab. 2010;95:2655-63.

57  Peccin S, de Castsro JA, Furlanetto TW, Furtado AP, Brasil BA, Czepielewski MA. Ultrasonography: is it useful in the diagnosis of cancer in thyroid nodules? J Endocrinol Invest. 2002;25:39-43.
-5858  Alexander EK, Marqusee E, Orcutt J, Benson CB, Frates MC, Doubilet PM, et al. Thyroid nodule shape and prediction of malignancy. Thyroid. 2004;14:953-8.) (B). Findings suggestive of neck metastases or calcitonin levels > 400 pg/mL indicate the need for additional tests (6 Cohen R, Campos JM, Salaun C, Heshmati HM, Kraimps JL, Proye C, et al. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d’Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab. 2000;85:919-22.,7 Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab. 2005;90:2029-34.) (B). It is worth noting that the radiological detection of distant metastases is quite improbable when the calcitonin levels are < 250 pg/mL (6868  Yen TW, Shapiro SE, Gagel RF, Sherman SI, Lee JE, Evans DB. Medullary thyroid carcinoma: results of a standardized surgical approach in a contemporary series of 80 consecutive patients. Surgery. 2003;134:890-9.) (B). The most efficacious approach to diagnosing distant metastases includes a combination of CT of the neck and chest and magnetic resonance imaging (MRI) of the liver (1010  Giraudet AL, Vanel D, Leboulleux S, Auperin A, Dromain C, Chami L, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 2007;92:4185-90.) (B). The risk of distant metastases is similar in individuals with sporadic or hereditary MTC (7 Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab. 2005;90:2029-34.) (B).

Pheochromocytoma is a tumor that originates in the chromaffin cells of the adrenal medulla and occurs in approximately 30-50% of individuals with MEN 2A or 2B. Adrenomedullary disease is more frequently bilateral (up to 78% of cases) in MEN 2, thus contrasting with sporadic pheochromocytoma, which usually appears as a single unilateral lesion. Additionally, pheochromocytoma tends to appear earlier in individuals with MEN 2 and seldom metastasizes. The clinical manifestations of pheochromocytoma are caused by catecholamine hypersecretion and include the most frequent manifestations of arterial hypertension, tachycardia, headaches, and excessive sweating (6969  Kramer CK, Leitão CB, Azevedo MJ, Canani LH, Maia AL, Czepielewski M, et al. Degree of catecholamine hypersecretion is the most important determinant of intra-operative hemodynamic outcomes in pheochromocytoma. J Endocrinol Invest. 2009;32:234-7.,7070  Pereira MA, Souza BF, Freire DS, Lucon AM. [Pheochromocytoma]. Arq Bras Endocrinol Metabol. 2004;48:751-75.) B/C). Nevertheless, some individuals might merely exhibit a discrete increase in catecholamine levels that is unattended by any signs or symptoms (7171  Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005;366:665-75.) (D).

Individuals with hereditary MTC should be screened for pheochromocytoma, given their high risk of that disease (7272  Machens A, Brauckhoff M, Holzhausen HJ, Thanh PN, Lehnert H, Dralle H. Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2005;90:3999-4003.) (B). As up to 10% of apparently sporadic MTC have a RET germline mutation, the presence of pheochromocytoma should be excluded in any patient with suspected MTC before the thyroidectomy, due to the high risk of anesthesia and the surgical procedure (7373  Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612.,7474  Rodriguez JM, Balsalobre M, Ponce JL, Rios A, Torregrosa NM, Tebar J, et al. Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World J Surg. 2008;32:2520-6.)(D/B). A pheochromocytoma diagnosis is based on the identification of excessive catecholamine production by measuring the plasma and/or urine catecholamine and/or metanephrine levels. The measurement of plasma fractionated metanephrines seems to be the most useful test in cases of hereditary pheochromocytoma, with sensitivity and specificity rates of 99% and 98%, respectively. The sensitivity and specificity rates of urine metanephrines, plasma catecholamines, and urine catecholamines are 97-100% and 93-94%, 76-84% and 81-88%, and 84-86% and 88-99%, respectively (7575  Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA. 2002;287:1427-34.,7676  Boyle JG, Davidson DF, Perry CG, Connell JM. Comparison of diagnostic accuracy of urinary free metanephrines, vanillyl mandelic Acid, and catecholamines and plasma catecholamines for diagnosis of pheochromocytoma. J Clin Endocrinol Metab. 2007;92:4602-8.) (B). Therefore, normal fractionated plasma metanephrines levels practically rule out pheochromocytoma in high-risk patients such as those with genetic syndromes (7777  Sawka AM, Jaeschke R, Singh RJ, Young WF Jr. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab. 2003;88:553-8.

78  Eisenhofer G, Goldstein DS, Walther MM, Friberg P, Lenders JW, Keiser HR, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab. 2003;88:2656-66.
-7979  Pacak K, Ilias I, Adams KT, Eisenhofer G. Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med. 2005;257:60-8.) (B/B/D). When plasma fractionated metanephrine measurements are unavailable, urine levels might be assessed.

Computed tomography or MRI of the abdomen might be performed to identify the localization of a pheochromocytoma. CT of the abdomen was able to identify the localization of hereditary adrenal tumors in 76% of the evaluated cases (8080  Pomares FJ, Canas R, Rodriguez JM, Hernandez AM, Parrilla P, Tebar FJ. Differences between sporadic and multiple endocrine neoplasia type 2A phaeochromocytoma. Clin Endocrinol (Oxf). 1998;48:195-200.) (B). Some CT-detectable nodule features might be helpful for the differential diagnosis among various types of adrenal lesions, including adenoma, pheochromocytoma, and carcinoma. The lesion density is 1 of the parameters that helps to distinguish adrenal adenomas from non-adenomas because adenoma densities are low due to their high intracellular lipid contents. CT densities are measured in Hounsfield units (HU); with a cutoff point of 10 HU, non-contrast-enhanced CT exhibits a 75% sensitivity rate and 100% specificity rate for the differentiation between adrenal adenomas and non-adenomas. Adenoma densities are usually lower than those of other tumors (pheochromocytoma, carcinoma), and contrast washout occurs faster in adenomas, compared to other adrenal lesions. A > 50% washout at 10 minutes after administration exhibits 100% sensitivity and specificity for the identification of adrenal adenomas, compared to pheochromocytomas, carcinomas, and metastatic lesions (8181  Hamrahian AH, Ioachimescu AG, Remer EM, Motta-Ramirez G, Bogabathina H, Levin HS, et al. Clinical utility of noncontrast computed tomography attenuation value (hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience. J Clin Endocrinol Metab. 2005;90:871-7.

82  Szolar DH, Korobkin M, Reittner P, Berghold A, Bauernhofer T, Trummer H, et al. Adrenocortical carcinomas and adrenal pheochromocytomas: mass and enhancement loss evaluation at delayed contrast-enhanced CT. Radiology. 2005;234:479-85.
-8383  Pena CS, Boland GW, Hahn PF, Lee MJ, Mueller PR. Characterization of indeterminate (lipid-poor) adrenal masses: use of washout characteristics at contrast-enhanced CT. Radiology. 2000;217:798-802.) (B).

Hyperparathyroidism occurs in approximately 10-20% of individuals with MEN 2A and is either asymptomatic or presents with manifestations secondary to hypercalcemia (8484  Kouvaraki MA, Shapiro SE, Perrier ND, Cote GJ, Gagel RF, Hoff AO, et al. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005;15:531-44.) (D). In suspected cases of hereditary MTC associated with MEN 2A, a serum albumin-adjusted calcium measurement should be included in the preoperative investigation (7373  Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612.,8585  Schuffenecker I, Virally-Monod M, Brohet R, Goldgar D, Conte-Devolx B, Leclerc L, et al. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D’etude des Tumeurs à Calcitonine. J Clin Endocrinol Metab. 1998;83(2):487-91.) (D).

Recommendation 6 (Flowchart 1)

Neck US must be performed in all affected individuals for detection of locoregional metastases. In individuals with suspected locoregional metastases or calcitonin levels > 400 pg/mL, the presence of distant metastases must be investigated before surgery (Recommendation B). The presence of pheochromocytoma must be investigated by the measurement of plasma fractionated metanephrines or urine metanephrine levels, if not available the blood measurement (Recommendation B). Once the diagnosis is confirmed, the adrenal tumor must be removed before thyroidectomy (Recommendation B). The presence of hyperparathyroidism might be investigated through a serum calcium level measurement after adjusting for the albumin concentration (Recommendation D).

7. Which individuals with confirmed or suspected MTC should be subjected to RET proto-oncogene molecular testing?

The RET proto-oncogene comprises 21 exons and encodes a tyrosine-kinase receptor that is expressed in neural crest-derived cells, including the thyroid C cells, adrenal medulla, and parathyroid glands. The RET protein comprises 3 domains: an extracellular cysteine-rich domain with cadherin-like repeats, a transmembrane domain, and an intracellular domain with 2 tyrosine-kinase domains (TK1 and TK2). Hereditary MTC affects approximately 1 in every 30,000 individuals and is caused by germline mutations in the RET proto-oncogene, an autosomal dominant genetic syndrome with approximately 100% penetrance and a variable phenotype. The mutations mainly affect the RET exons 10, 11, and 16, and less commonly the exons 5, 8, 13, 14, and 15 (8484  Kouvaraki MA, Shapiro SE, Perrier ND, Cote GJ, Gagel RF, Hoff AO, et al. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005;15:531-44.,8686  Ceolin L, Siqueira DR, Romitti M, Ferreira CV, Maia AL. Molecular basis of medullary thyroid carcinoma: the role of RET polymorphisms. Int J Mol Sci. 2012;13:221-39.) (D).

Several studies have found correlations between specific RET mutations and the various clinical syndromes associated with MEN 2. Mutations at codon 634 (exon 11) are associated with the presence of pheochromocytoma and/or hyperparathyroidism, while mutations at codon 918 (exon 16) are specific for MEN 2B. Similarly, mutations at codons 768 and 804 are associated with FMTC (Table 2) (8787  Machens A, Gimm O, Hinze R, Hoppner W, Boehm BO, Dralle H. Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties. J Clin Endocrinol Metab. 2001;86:1104-9.,8888  Ponder BA. The phenotypes associated with RET mutations in the multiple endocrine neoplasia type 2 syndrome. Cancer Res. 1999;59:1736s-41s.) (B/D).

Table 2
Correlations between the clinical presentations and germline RET mutations in hereditary medullary thyroid carcinoma

Molecular diagnosis is superior to clinical and/or biochemical diagnosis for the identification of asymptomatic individuals who are at risk of neoplasia (8989  Lips CJ, Landsvater RM, Hoppener JW, Geerdink RA, Blijham G, van Veen JM, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med. 1994;331:828-35.

90  Vieira AE, Mello MP, Elias LL, Lau IF, Maciel LM, Moreira AC, et al. Molecular and biochemical screening for the diagnosis and management of medullary thyroid carcinoma in multiple endocrine neoplasia type 2A. Horm Metab Res. 2002;34:202-6.
-9191  Frilling A, Dralle H, Eng C, Raue F, Broelsch CE. Presymptomatic DNA screening in families with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Surgery. 1995;118:1099-103.) (B/C/B). Molecular testing allows the identification of the RET mutations that cause MEN 2A and MEN 2B in 95–100% of the evaluated cases (9292  Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996;276:1575-9.,9393  Bugalho MJ, Domingues R, Santos JR, Catarino AL, Sobrinho L. Mutation analysis of the RET proto-oncogene and early thyroidectomy: results of a Portuguese cancer centre. Surgery. 2007;141:90-5.) (B/D).

Genetic screening should be performed in all individuals with MTC, rather than in the cases suspected of the hereditary form only, as 4-10% of apparently sporadic MTCs exhibit germline RET mutations; these occur particularly among young patients and/or those with multifocal disease (4242  Elisei R, Bottici V, Luchetti F, Di Coscio G, Romei C, Grasso L, et al. Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. J Clin Endocrinol Metab. 2004;89:163-8.,9494  Wiench M, Wygoda Z, Gubala E, Wloch J, Lisowska K, Krassowski J, et al. Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients. J Clin Oncol. 2001;19:1374-80.

95  Elisei R, Romei C, Cosci B, Agate L, Bottici V, Molinaro E, et al. RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab. 2007;92:4725-9.
-9696  Romei C, Cosci B, Renzini G, Bottici V, Molinaro E, Agate L, et al. RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC). Clin Endocrinol (Oxf). 2011;74:241-7.) (B).

Therefore, investigations of RET proto-oncogene mutations are of paramount importance in the diagnostic assessment of and therapeutic planning for individuals with MTC.

Recommendation 7

A molecular assessment is indicated for all individuals with C cell hyperplasia, (familial or apparently sporadic) MTC, and/or MEN 2 (Recommendation B). The molecular diagnosis might guide the choice of therapeutic procedures and consequently change the natural course of disease, indicate genetic counseling, and help to establish the disease prognosis (Recommendation B).

8. When should the relatives of individuals with MTC be assessed? What is the relevance of a RET molecular assessment in such individuals?

Hereditary MTC is an autosomal dominant disease, and therefore the likelihood of transmission from 1 generation to the next is 50% (8989  Lips CJ, Landsvater RM, Hoppener JW, Geerdink RA, Blijham G, van Veen JM, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med. 1994;331:828-35.) (B). Following the identification of a RET mutation in an individual (proband), all of his or her first-degree relatives should be subjected to genetic assessment. The molecular analysis of the RET proto-oncogene in a proband’s relatives is of paramount importance because it allows for early diagnosis and treatment and consequently better prognosis (8787  Machens A, Gimm O, Hinze R, Hoppner W, Boehm BO, Dralle H. Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties. J Clin Endocrinol Metab. 2001;86:1104-9.,9393  Bugalho MJ, Domingues R, Santos JR, Catarino AL, Sobrinho L. Mutation analysis of the RET proto-oncogene and early thyroidectomy: results of a Portuguese cancer centre. Surgery. 2007;141:90-5.) (B). For these reasons, the indication of molecular testing is considered essential and is recommended in the guidelines developed by the American Thyroid Association (ATA) and the European Thyroid Association (ETA), as well as in the Clinical Guidelines on Medullary Thyroid Carcinoma for Private Health Insurance and Plans from the Brazilian Medical Association and the National Regulatory Agency for Private Health Insurance and Plans (7373  Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612., 9797  Maia AL, Puñales MK, Mazeto G, Caldas G, Ward LS, Kimura ET, et al. Carcinoma medular de tireoide: diagnóstico. Diretrizes Clínicas na Saúde Suplementar da Associação Médica Brasileira e Agência Nacional de Saúde Suplementar 2011. Disponível em: http://www.projetodiretrizes.org.br/ans/diretrizes/cancer_medular_de_tireoide-diagnostico.pdf. Acesso em: 1 Out, 2014.
http://www.projetodiretrizes.org.br/ans/...
,9898  Elisei R, Alevizaki M, Conte-Devolx B, Frank-Raue K, Leite V, Williams GR. 2012 European thyroid association guidelines for genetic testing and its clinical consequences in medullary thyroid cancer. Eur Thyroid J. 2013;1:216-31.) (D).

Total thyroidectomy should be considered in asymptomatic carriers of RET mutations (7373  Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612.,8989  Lips CJ, Landsvater RM, Hoppener JW, Geerdink RA, Blijham G, van Veen JM, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med. 1994;331:828-35.) (D/B). The appropriate age for prophylactic surgery depends on the results of RET molecular testing, the clinical data, and the serum calcitonin levels. The various mutation types correlate with the degree of MTC aggressiveness, and therefore molecular testing facilitates decision-making with respect to the extent of surgery and the age at which surgery should performed. Additionally, the preoperative serum calcitonin levels contribute to surgery planning and the establishment of disease prognosis, in addition to being used in postoperative follow-ups (6 Cohen R, Campos JM, Salaun C, Heshmati HM, Kraimps JL, Proye C, et al. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d’Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab. 2000;85:919-22.,9999  Miccoli P, Elisei R, Donatini G, Materazzi G, Berti P. Video-assisted central compartment lymphadenectomy in a patient with a positive RET oncogene: initial experience. Surg Endosc. 2007;21:120-3.,100100  Punales MK, da Rocha AP, Meotti C, Gross JL, Maia AL. Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A. Thyroid. 2008;18:1261-8.) (B/C/B). The presence of neck metastases should be also investigated with physical examinations and US before surgery (6060  Saller B, Moeller L, Gorges R, Janssen OE, Mann K. Role of conventional ultrasound and color Doppler sonography in the diagnosis of medullary thyroid carcinoma. Exp Clin Endocrinol Diabetes. 2002;110:403-7.,6262  Kouvaraki MA, Shapiro SE, Fornage BD, Edeiken-Monro BS, Sherman SI, Vassilopoulou-Sellin R, et al. Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer. Surgery. 2003;134:946-54.,100100  Punales MK, da Rocha AP, Meotti C, Gross JL, Maia AL. Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A. Thyroid. 2008;18:1261-8.) (B).

Based on genotype-phenotype correlation studies, ATA formulated a series of recommendations for prophylactic thyroidectomy in asymptomatic RET mutation carriers. The different types of mutations are classified in 4 risk-based categories according to the tumor aggressiveness (A < B < C < D). In individuals with ATA A and B mutations (codons 768, 790, 791, 804 and 891 and 609, 611, 618, 620, and 630, respectively), the risk of MTC is moderate, and in most cases, prophylactic surgery might be performed after the age of 5 years. Individuals with mutations in codon 634 (ATA risk level C) are at risk of developing MTC early in life, and prophylactic surgery should be performed before the age of 5 years (101101  Machens A, Lorenz K, Dralle H. Progression of medullary thyroid cancer in RET carriers of ATA class A and C mutations. J Clin Endocrinol Metab. 2014;99:E286-92.) (B). Individuals with phenotype MEN 2B-associated mutations (ATA risk level D) have an even higher risk of early MTC development and therefore should be subjected to prophylactic thyroidectomy prior to 1 year of age or at the time of diagnosis (7373  Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612.) (D).

In children and young adults with RET mutations, the presence of a palpable thyroid nodule at the time of diagnosis correlates strongly with persistent or recurrent MTC (100100  Punales MK, da Rocha AP, Meotti C, Gross JL, Maia AL. Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A. Thyroid. 2008;18:1261-8.) (B). Those data reinforce the relevance of the early investigation of RET mutations.

Relatives who test negative for RET mutations are considered to have no risk of MTC and/or associated neoplasms and might thus be released from further follow-up.

Recommendation 8

All first-degree relatives of individuals with MTC and germline RET mutations should be subjected to molecular screening (Recommendation B).

9. Does the mutation type interfere with the clinical presentation of MTC?

Most families with MEN 2A exhibit mutations in 1 of the 5 cysteine residues in exon 10 (codons 609, 611, 618, and 620) or 11 (codon 634) of the RET extracellular domain (Table 2). All mutations in codon 634 are associated with pheochromocytoma and/or hyperparathyroidism (8787  Machens A, Gimm O, Hinze R, Hoppner W, Boehm BO, Dralle H. Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties. J Clin Endocrinol Metab. 2001;86:1104-9.,9292  Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996;276:1575-9.) (B). Specific amino acid changes in the same codon interfere with the genotype-phenotype correlation. In individuals with MEN 2A, mutation C634R is associated with a higher rate of metastasis at the time of diagnosis, compared to mutations C634W and C634Y (102102  Punales MK, Graf H, Gross JL, Maia AL. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003;88:2644-9.) (B).

The risk of pheochromocytoma in individuals with MEN 2 varies as a function of the mutated codon. The adrenal tumor occurrence rates are 28%, 21%, and 3% in carriers of mutations in the highest-risk category (mutations in codon 918), in the high-risk category (mutations in codons 634, 630, 609, 611, 618, and 620), and in the lower-risk category (mutations in codons 768, 790, 791, 804, and 891) (7272  Machens A, Brauckhoff M, Holzhausen HJ, Thanh PN, Lehnert H, Dralle H. Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2005;90:3999-4003.) (B). Mutation C634W correlates strongly with a high penetrance of pheochromocytoma (103103  Milos IN, Frank-Raue K, Wohllk N, Maia AL, Pusiol E, Patocs A, et al. Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation. Endocr Relat Cancer. 2008;15:1035-41.) (B).

A specific mutation in codon 16 (M918T) has been found in approximately 95% of individuals with MEN 2B, the mutation A883F (exon 15) has been identified in 2-3% of the cases, and the double mutation V804M/Y806C (exon 14) in the same allele has been described in 1 patient with MEN 2B. Mutations in codons 883 and 918 correlate with the occurrence of MTC at a younger age, an increased risk of metastasis, and an increased disease-specific mortality (8686  Ceolin L, Siqueira DR, Romitti M, Ferreira CV, Maia AL. Molecular basis of medullary thyroid carcinoma: the role of RET polymorphisms. Int J Mol Sci. 2012;13:221-39.,9292  Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996;276:1575-9.,104104  Pelizzo MR, Boschin IM, Bernante P, Toniato A, Piotto A, Pagetta C, et al. Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. Eur J Surg Oncol. 2007;33:493-7.) (D/B/B).

Approximately 90% of families with hereditary MTC exhibit mutations in RET exon 10 (codons 609, 611, 618, and 620) and exon 11 (codon 634) (6 Cohen R, Campos JM, Salaun C, Heshmati HM, Kraimps JL, Proye C, et al. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d’Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab. 2000;85:919-22.,1010  Giraudet AL, Vanel D, Leboulleux S, Auperin A, Dromain C, Chami L, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 2007;92:4185-90.) (B). Substitutions in the tyrosine-kinase domain-coding exons 13 (codons 768, 790, and 791), 14 (codons 804 and 844), and 15 (codon 891) are less common. In such cases, MTC appears later, and the prognosis is more favorable compared to that of other forms of MTC (9292  Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996;276:1575-9.) (B).

However, it is worth noting that individuals from the same family who carry the same RET mutation can exhibit variable phenotypic expressions and degrees of tumor aggressiveness (102102  Punales MK, Graf H, Gross JL, Maia AL. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003;88:2644-9.) (B). In recent years, the presence of RET gene variants or polymorphisms has been associated with changes in the clinical presentation and natural history of MEN 2 (8686  Ceolin L, Siqueira DR, Romitti M, Ferreira CV, Maia AL. Molecular basis of medullary thyroid carcinoma: the role of RET polymorphisms. Int J Mol Sci. 2012;13:221-39.,105105  Siqueira DR, Ceolin L, Ferreira CV, Romitti M, Maia SC, Zanini Maciel LM, et al. Role of ret genetic variants in MEN 2-associated pheochromocytoma. Eur J Endocrinol. 2014;170:821-8.) (D/B).

Recommendation 9

The knowledge of the type of RET mutation provides relevant information about the clinical presentation of MEN 2 and the biological behaviors of the associated neoplasms (Recommendation B).

10. In addition to endocrine tumors, what are the clinical manifestations associated with RET proto-oncogene mutations?

In addition to pheochromocytoma and hyperparathyroidism, hereditary MTC is rarely associated with cutaneous lichen amyloidosis and Hirschsprung’s disease (106106  Nunziata V, Giannattasio R, Di Giovanni G, D’Armiento MR, Mancini M. Hereditary localized pruritus in affected members of a kindred with multiple endocrine neoplasia type 2A (Sipple’s syndrome). Clin Endocrinol (Oxf). 1989;30:57-63.

107  Gagel RF, Levy ML, Donovan DT, Alford BR, Wheeler T, Tschen JA. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med. 1989;111:802-6.
-108108  Vaclavikova E, Kavalcova L, Skaba R, Dvorakova S, Macokova P, Rouskova B, et al. Hirschsprung’s disease and medullary thyroid carcinoma: 15-year experience with molecular genetic screening of the RET proto-oncogene. Pediatr Surg Int. 2012;28(2):123-8.) (C/B/D).

Cutaneous lichen amyloidosis (CLA) is an itchy hyperpigmented skin lesion that appears on the upper area of the back (interscapular region). The association between mutations in RET codon 634 and CLA was first described in 1989 (106106  Nunziata V, Giannattasio R, Di Giovanni G, D’Armiento MR, Mancini M. Hereditary localized pruritus in affected members of a kindred with multiple endocrine neoplasia type 2A (Sipple’s syndrome). Clin Endocrinol (Oxf). 1989;30:57-63.) (B). CLA can appear early and usually precedes thyroid disease (106106  Nunziata V, Giannattasio R, Di Giovanni G, D’Armiento MR, Mancini M. Hereditary localized pruritus in affected members of a kindred with multiple endocrine neoplasia type 2A (Sipple’s syndrome). Clin Endocrinol (Oxf). 1989;30:57-63.,107107  Gagel RF, Levy ML, Donovan DT, Alford BR, Wheeler T, Tschen JA. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med. 1989;111:802-6.) (C/B).

Inactivating RET germline mutations appear in 10-40% of cases of Hirschsprung’s disease; this disease comprises the congenital absence of the intestinal intermuscular (Auerbach’s), and superficial (Meissner’s) and deep (Henle’s) submucosal plexuses, leading to symptoms of intestinal obstruction during the neonatal period, as well as constipation, abdominal distension, and vomiting in adulthood. Mutations in exon 10 are associated with the concomitant occurrence of MEN 2 and Hirschsprung’s disease (108108  Vaclavikova E, Kavalcova L, Skaba R, Dvorakova S, Macokova P, Rouskova B, et al. Hirschsprung’s disease and medullary thyroid carcinoma: 15-year experience with molecular genetic screening of the RET proto-oncogene. Pediatr Surg Int. 2012;28(2):123-8.) (B). The affected individuals carry a single mutation, thus suggesting that the effects of that mutation vary as a function of the tissues in which RET is expressed (109109  Romeo G, Ceccherini I, Celli J, Priolo M, Betsos N, Bonardi G, et al. Association of multiple endocrine neoplasia type 2 and Hirschsprung disease. J Intern Med. 1998;243:515-20.) (C).

Recommendation 10

The presence of CLA or Hirschsprung’s disease indicates the suspected occurrence of hereditary MTC and therefore the need to perform a RET molecular assessment (Recommendation B).

11. When and how to screen for pheochromocytoma and hyperparathyroidism?

MEN 2A is the most common form of MEN and is characterized by the occurrence of MTC, pheochromocytoma, and hyperparathyroidism. MTC occurs in 95% of individuals with MEN 2A, while the risks of unilateral or bilateral pheochromocytoma and hyperparathyroidism are 57%, and 15-30%, respectively (8484  Kouvaraki MA, Shapiro SE, Perrier ND, Cote GJ, Gagel RF, Hoff AO, et al. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005;15:531-44.,110110  Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86:5658-71.) (D/D). Adrenal disease is usually benign, multicentric, and bilateral, and, as a rule, it is detected after the onset of MTC. Hyperparathyroidism usually involves all of the parathyroid glands, and gland hyperplasia is the most commonly detected histological lesion in early-stage disease. However, when diagnosis is delayed, adenoma occurs concomitantly with hyperplasia (8484  Kouvaraki MA, Shapiro SE, Perrier ND, Cote GJ, Gagel RF, Hoff AO, et al. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005;15:531-44.) (D). MEN 2B is the less common variety of MEN 2 and exhibits a more aggressive form of MTC, as well as the occurrence of pheochromocytoma; however, hyperparathyroidism does not occur (8484  Kouvaraki MA, Shapiro SE, Perrier ND, Cote GJ, Gagel RF, Hoff AO, et al. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005;15:531-44.) (D).

A recent study assessed the mean age at onset of pheochromocytoma in individuals with MEN 2A, according to the ATA risk categories described above. The authors found that the first pheochromocytomas were diagnosed at ages 25, 34, 40, and 56 year old in individuals classified as ATA risk levels D, C, B, and A, respectively and that the occurrence frequencies were 27, 32, 17, and 3% in categories D, C, B, and A, respectively (111111  Machens A, Lorenz K, Dralle H. Peak incidence of pheochromocytoma and primary hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening. J Clin Endocrinol Metab. 2013;98:E336-45.) (B).

The youngest ages at pheochromocytoma diagnosis were 12 and 5 years old in carriers of mutations in codons 918 and 634, respectively (7272  Machens A, Brauckhoff M, Holzhausen HJ, Thanh PN, Lehnert H, Dralle H. Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2005;90:3999-4003.,112112  Romei C, Pardi E, Cetani F, Elisei R. Genetic and clinical features of multiple endocrine neoplasia types 1 and 2. J Oncol. 2012;2012:705036.,113113  Skinner MA, DeBenedetti MK, Moley JF, Norton JA, Wells SA Jr. Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg. 1996;31:177-81.) (B/D/B). Less aggressive mutations such as those in codons 609, 611, and 618 and in codons 768, 790, and 891 are associated with a later onset of pheochromocytoma, specifically at ages 19 and 28 years old, respectively (7272  Machens A, Brauckhoff M, Holzhausen HJ, Thanh PN, Lehnert H, Dralle H. Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2005;90:3999-4003.,114114  Quayle FJ, Fialkowski EA, Benveniste R, Moley JF. Pheochromocytoma penetrance varies by RET mutation in MEN 2A. Surgery. 2007;142:800-5.) (B/B). Therefore, the investigation of adrenal tumors in patients with MEN 2 should begin at 8 years of age in carriers of mutations in codons 918, 634, and 630, and after 20 years of age in the remainder of the cases (7272  Machens A, Brauckhoff M, Holzhausen HJ, Thanh PN, Lehnert H, Dralle H. Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2005;90:3999-4003.) (B). Assessments might be performed by measuring the plasma or urine metanephrine levels (7777  Sawka AM, Jaeschke R, Singh RJ, Young WF Jr. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab. 2003;88:553-8.

78  Eisenhofer G, Goldstein DS, Walther MM, Friberg P, Lenders JW, Keiser HR, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab. 2003;88:2656-66.
-7979  Pacak K, Ilias I, Adams KT, Eisenhofer G. Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med. 2005;257:60-8.) (B/B/D). The ruling out of pheochromocytoma is of paramount importance in cases of hereditary MTC because the adrenal tumor should be treated before the thyroidectomy.

Hyperparathyroidism rarely occurs in children, as the mean age at diagnosis is 38 years old in individuals with MEN 2A (115115  Kraimps JL, Denizot A, Carnaille B, Henry JF, Proye C, Bacourt F, et al. Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d’Etude des Tumeurs a Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons. World J Surg. 1996;20:808-12.,116116  Raue F, Kraimps JL, Dralle H, Cougard P, Proye C, Frilling A, et al. Primary hyperparathyroidism in multiple endocrine neoplasia type 2A. J Intern Med. 1995;238:369-73.) (B/B). Serum calcium and albumin measurements should begin at 8 years of age in carriers of mutations in codons 630 and 634, and at 20 years of age in carriers of other mutations associated with MEN 2A, and should be repeated annually. Recently, a case of hyperparathyroidism diagnosed in a 5-year-old child with MEN 2A was reported (117117  Magalhaes PK, Antonini SR, de Paula FJ, de Freitas LC, Maciel LM. Primary hyperparathyroidism as the first clinical manifestation of multiple endocrine neoplasia type 2A in a 5-year-old child. Thyroid. 2011;21:547-50.) (C).

Recommendation 11

In asymptomatic cases or in the absence of adrenal masses, urine and/or fractionated plasma metanephrines measurements should begin at 8 years of age in individuals with MEN 2B or 2A who carry mutations in codons 630 or 634, and after 20 years of age in the remainder of individuals with MEN 2A.

Hyperparathyroidism screening must be performed annually by measuring the total calcium and albumin levels, starting at 8 years age in carriers of mutations in RET codons 630 and 634 and at 20 years of age in the remainder of individuals with MEN 2A.

PART II: MTC – SURGICAL TREATMENT

1. What is the surgical treatment for individuals with MTC limited to the thyroid gland?

Upon preoperative assessment, MTC is considered to be limited to the thyroid gland if there is no evidence of involvement of adjacent structures, or lymph node or distant metastases. In such cases, the indicated surgical treatment comprises total thyroidectomy with (elective) prophylactic dissection of the central compartment (levels VI and VII; Figure 1) (6666  Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer. 2000;88:1139-48.,118118  Machens A, Holzhausen HJ, Dralle H. Contralateral cervical and mediastinal lymph node metastasis in medullary thyroid cancer: systemic disease? Surgery. 2006;139:28-32.

119  Tavares MR, Michaluart P Jr, Montenegro F, Arap S, Sodre M, Takeda F, et al. Skip metastases in medullary thyroid carcinoma: a single-center experience. Surg Today. 2008;38:499-504.
-120120  Lupone G, Antonino A, Rosato A, Zenone P, Iervolino EM, Grillo M, et al. Surgical strategy for the treatment of sporadic medullary thyroid carcinoma: our experience. G Chir. 2012;33:395-9.) (B). Given the risk of hidden metastatic disease, prophylactic dissection of the lateral compartments might be added, particularly when the tumor is > 1 cm, if metastases are found in the central compartment, or elevated calcitonin levels (121121  Weber T, Schilling T, Frank-Raue K, Colombo-Benkmann M, Hinz U, Ziegler R, et al. Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas. Surgery. 2001;130:1044-9.

122  Machens A, Hauptmann S, Dralle H. Increased risk of lymph node metastasis in multifocal hereditary and sporadic medullary thyroid cancer. World J Surg. 2007;31:1960-5.
-123123  Dralle H, Machens A. Surgical management of the lateral neck compartment for metastatic thyroid cancer. Curr Opin Oncol. 2013;25:20-6.) (B/B/D).

Figure 1
Cervical lymph nodes anatomy.

Recommendation 1

The surgical treatment recommended for individuals with MTC limited to the thyroid gland is total thyroidectomy and elective dissection of the central compartment (Recommendation B).

2. What is the surgical approach for individuals with MTC and locoregional disease diagnosed during the preoperative assessment?

In individuals with MTC, the presence of locoregional disease indicates the need for a total thyroidectomy associated with dissection of the lymph nodes in the central compartment (levels VI and VII; Figure 1) (104104  Pelizzo MR, Boschin IM, Bernante P, Toniato A, Piotto A, Pagetta C, et al. Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. Eur J Surg Oncol. 2007;33:493-7.) (B). Lateral lymph node dissection (levels, II, III, IV, and V) is indicated when metastases are suspected in any of those levels (121121  Weber T, Schilling T, Frank-Raue K, Colombo-Benkmann M, Hinz U, Ziegler R, et al. Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas. Surgery. 2001;130:1044-9.) (B). The benefit of prophylactic lateral dissection when metastases are only located in the central compartment is controversial. Some authors support the US preoperative evaluation for the detection of metastases and argue against prophylactic dissection. However, due to the high incidence of lymph node metastases and the risk of occult metastatic disease, others indicate compartment oriented lymph node dissections in the first surgery because of the complications associated with re-interventions (7373  Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612.,121121  Weber T, Schilling T, Frank-Raue K, Colombo-Benkmann M, Hinz U, Ziegler R, et al. Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas. Surgery. 2001;130:1044-9.

122  Machens A, Hauptmann S, Dralle H. Increased risk of lymph node metastasis in multifocal hereditary and sporadic medullary thyroid cancer. World J Surg. 2007;31:1960-5.
-123123  Dralle H, Machens A. Surgical management of the lateral neck compartment for metastatic thyroid cancer. Curr Opin Oncol. 2013;25:20-6.) (D/B/B/D).

The current American Joint Committee on Cancer (AJCC) 6th edition TNM (tumor, node, metastasis) classification system is used for postoperative staging of MTC (Table 3) (124124  Greene FL, Page DL, Fleming ID, Fritz A, Balch DM. 2003 AJCC Cancer Staging Manual, 6th edition. Springer Verlag, Chicago.). The likelihood of a cure is low in cases with extrathyroid disease. The biochemical cure rates in individuals with preoperative basal calcitonin levels > 300 pg/mL, a primary tumor > 10 mm, and persistent metastatic disease after lymph node dissection are below 50% (7 Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab. 2005;90:2029-34.) (B). As a rule, only 10-40% of individuals with neck metastases achieve biochemical cures (7 Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab. 2005;90:2029-34.,119119  Tavares MR, Michaluart P Jr, Montenegro F, Arap S, Sodre M, Takeda F, et al. Skip metastases in medullary thyroid carcinoma: a single-center experience. Surg Today. 2008;38:499-504.) (B), while relapses occur in 3.3% of the individuals who attain normal basal calcitonin levels after a follow-up of 0.7-7.5 years (125125  Franc S, Niccoli-Sire P, Cohen R, Bardet S, Maes B, Murat A, et al. Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma. Clin Endocrinol (Oxf). 2001;55:403-9.) (B). Similar cure rates (~38%) are reported in individuals who are subjected to extensive surgery (7 Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab. 2005;90:2029-34.) (B). Therefore, as extensive surgery is not associated with higher cure rate, less aggressive procedures should be indicated in cases with advanced local disease or distant metastases in order to maintain control of local disease while preserving the parathyroid function, vocal cords, and deglutition (7373  Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612.,104104  Pelizzo MR, Boschin IM, Bernante P, Toniato A, Piotto A, Pagetta C, et al. Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. Eur J Surg Oncol. 2007;33:493-7.) (D/B).

Table 3
American Joint Committee on Cancer TNM Classification

Recommendation 2

In cases with locoregional disease, total thyroidectomy with central compartment lymph node dissection is indicated (Recommendation B). Lateral lymph node dissection is indicated when metastases are present or suspected (Recommendation B). Less aggressive surgery should be indicated in cases with advanced local disease and/or distant metastases to achieve local disease control while preserving the patient’s voice, deglutition, and parathyroid function (Recommendation B).

3. What is the management of individuals with postoperative diagnoses of MTC?

In individuals with MTC that was diagnosed after a total lobectomy (thyroid lobe and isthmus), thyroidectomy can be complemented by central compartment dissection or only expectant management in selected cases (126126  Ito Y, Miyauchi A, Yabuta T, Fukushima M, Inoue H, Tomoda C, et al. Alternative surgical strategies and favorable outcomes in patients with medullary thyroid carcinoma in Japan: experience of a single institution. World J Surg. 2009;33:58-66.,127127  Machens A, Dralle H. Biological relevance of medullary thyroid microcarcinoma. J Clin Endocrinol Metab. 2012;97:1547-53.) (B). According to some authors, the latter alternative might apply to individuals with undetectable calcitonin levels at 2 months after thyroidectomy, unifocal MTC limited to the gland, tumor-free surgical margins, the absence of C cell hyperplasia, the absence of neck lymph node metastases in physical examination or on US, and a diagnosis of sporadic MTC based on negative RET molecular testing (120120  Lupone G, Antonino A, Rosato A, Zenone P, Iervolino EM, Grillo M, et al. Surgical strategy for the treatment of sporadic medullary thyroid carcinoma: our experience. G Chir. 2012;33:395-9.,126126  Ito Y, Miyauchi A, Yabuta T, Fukushima M, Inoue H, Tomoda C, et al. Alternative surgical strategies and favorable outcomes in patients with medullary thyroid carcinoma in Japan: experience of a single institution. World J Surg. 2009;33:58-66.,127127  Machens A, Dralle H. Biological relevance of medullary thyroid microcarcinoma. J Clin Endocrinol Metab. 2012;97:1547-53.) (B).

Recommendation 3

Completion thyroidectomy and prophylactic central compartment dissection are indicated in patients with postoperative diagnoses of MTC (Recommendation B). Expectant management might be considered in selected cases (Recommendation B).

4. What is the approach to the parathyroid glands in surgery for MTC?

As a rule, normal parathyroid glands should be preserved when thyroidectomy is performed. However, those glands might be accidentally removed or their vascularization might be compromised during surgery, especially for those glands located in the lower poles. The risk increases when a central compartment dissection is performed (124124  Greene FL, Page DL, Fleming ID, Fritz A, Balch DM. 2003 AJCC Cancer Staging Manual, 6th edition. Springer Verlag, Chicago.,125125  Franc S, Niccoli-Sire P, Cohen R, Bardet S, Maes B, Murat A, et al. Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma. Clin Endocrinol (Oxf). 2001;55:403-9.) (D/B). When devascularization occurs, the affected glands should be grafted onto the sternocleidomastoid muscle. In cases with a risk of hyperparathyroidism, such as the presence of MEN 2A-related mutations, grafting should be performed in the non-dominant forearm to facilitate the gland removal procedure in the event of recurrent hyperparathyroidism (128128  van Heerden JA, Kent RB 3rd, Sizemore GW, Grant CS, ReMine WH. Primary hyperparathyroidism in patients with multiple endocrine neoplasia syndromes. Surgical experience. Arch Surg. 1983;118:533-6.

129  Herfarth KK, Bartsch D, Doherty GM, Wells SA Jr, Lairmore TC. Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Surgery. 1996;120:966-73.
-130130  Scholten A, Schreinemakers JM, Pieterman CR, Valk GD, Vriens MR, Borel Rinkes IH. Evolution of surgical treatment of primary hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Endocr Pract. 2011;17:7-15.) (B).

The hyperparathyroidism occurs in approximately 10 to 20% of patients with MEN 2A. It is usually associated with mild and often asymptomatic disease, especially in young patients. When indicated treatment, it is important to establish whether the disease is restricted to one or multiple glands and then, decide the most appropriate surgical procedure. The following surgical procedures may be used, depending on the number of glands involved: total parathyroidectomy with autotransplantation, subtotal parathyroidectomy, or removal of a single gland (128128  van Heerden JA, Kent RB 3rd, Sizemore GW, Grant CS, ReMine WH. Primary hyperparathyroidism in patients with multiple endocrine neoplasia syndromes. Surgical experience. Arch Surg. 1983;118:533-6.,129129  Herfarth KK, Bartsch D, Doherty GM, Wells SA Jr, Lairmore TC. Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Surgery. 1996;120:966-73.) (B). The occurrence of permanent hypoparathyroidism is usually associated with total parathyroidectomy, although also already been reported after subtotal parathyroidectomy, or even after excision of two glands (130130  Scholten A, Schreinemakers JM, Pieterman CR, Valk GD, Vriens MR, Borel Rinkes IH. Evolution of surgical treatment of primary hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Endocr Pract. 2011;17:7-15.) (D). In cases of hyperparathyroidism that appear in individuals who previously underwent surgery for MTC, the affected gland should be identified via imaging methods such as US, CT, or sestamibi scintigraphy before surgery (129129  Herfarth KK, Bartsch D, Doherty GM, Wells SA Jr, Lairmore TC. Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Surgery. 1996;120:966-73.,131131  Olson JA Jr, DeBenedetti MK, Baumann DS, Wells SA Jr. Parathyroid autotransplantation during thyroidectomy. Results of long-term follow-up. Ann Surg. 1996;223:472-8.) (B). The successful use of calcimimetics has been reported in cases of persistent hyperparathyroidism (132132  Marcocci C, Chanson P, Shoback D, Bilezikian J, Fernandez-Cruz L, Orgiazzi J, et al. Cinacalcet reduces serum calcium concentrations in patients with intractable primary hyperparathyroidism. J Clin Endocrinol Metab. 2009;94:2766-72.) (B).

Recommendation 4

In cases without preoperative hyperparathyroidism, the “in situ” preservation of the parathyroid glands is always desirable. When the glands are accidentally removed or there is a risk of devascularization, the glands should be autografted into the sternocleidomastoid muscle (Recommendation B). In cases with hyperparathyroidism, MEN 2A, or prior surgery for MTC, the affected parathyroid gland should be identified with imaging methods to decide upon a subtotal or total parathyroidectomy, followed by a forearm autograft (Recommendation B).

5. What is the surgical approach in asymptomatic individuals with RET mutations?

Asymptomatic individuals with RET proto-oncogene mutations should be assessed before surgery by measuring the serum calcitonin levels and using neck US to identify the presence of thyroid nodules and lymph node metastases, as these indicate the need for a different surgical approach (6 Cohen R, Campos JM, Salaun C, Heshmati HM, Kraimps JL, Proye C, et al. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d’Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab. 2000;85:919-22.,6464  Ahn JE, Lee JH, Yi JS, Shong YK, Hong SJ, Lee DH, et al. Diagnostic accuracy of CT and ultrasonography for evaluating metastatic cervical lymph nodes in patients with thyroid cancer. World J Surg. 2008;32:1552-8.) (B). In such cases, the ATA guidelines recommend the application of a risk categorization system relative to the minimum age at the onset of MTC and the tumor aggressiveness, including the likelihood of metastasis, likelihood of cure, morbidity, and mortality (7373  Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612.,133133  Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendtro K, Chan JA, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013;42:557-77.) (D). That system clusters codons into risk levels ranging from A (least aggressive) to D (most aggressive; see Part I: MTC – Diagnosis – Question 8 of the present consensus). Based on the risk level that corresponds to the affected RET codon, therapeutic decision-making is performed according to the best age for so-called prophylactic thyroidectomy and the need for neck dissection. Preferably, the surgical approach should be performed in reference centers with experienced surgeons and a large volume of thyroid surgeries.

Additionally, the likelihood of pheochromocytoma onset and the age at which to begin investigating this onset are estimated according to those risk levels (see Part I: MTC – Diagnosis – Question 6 of the present consensus). When pheochromocytoma is diagnosed, it should be subjected to surgical treatment before MTC (122122  Machens A, Hauptmann S, Dralle H. Increased risk of lymph node metastasis in multifocal hereditary and sporadic medullary thyroid cancer. World J Surg. 2007;31:1960-5.,134134  Skinner MA, Moley JA, Dilley WG, Owzar K, Debenedetti MK, Wells SA Jr. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med. 2005;353:1105-13.,135135  Greenblatt DY, Elson D, Mack E, Chen H. Initial lymph node dissection increases cure rates in patients with medullary thyroid cancer. Asian J Surg. 2007;30:108-12.) (B).

Recommendation 5

The surgical approach in asymptomatic individuals with RET proto-oncogene mutations should consider the risk stratification according to the codon that exhibits the mutation, as follows:

Group D (MEN 2B): total thyroidectomy in the first year of life; if there is evidence of lymph node metastases, the thyroid nodule is > 5 mm, or the serum calcitonin level is > 40 pg/mL, central compartment dissection is also indicated. Individuals older than 1 year of age are indicated for (elective) “prophylactic” central dissection.

Group C: total thyroidectomy before 5 years of age.

Groups A and B: total thyroidectomy after 5 years of age if there is a lack of evidence for MTC (normal basal serum calcitonin levels and normal neck US).

Individuals in groups A, B, and C should only be subjected to central compartment dissection if there is clinical and/or imaging evidence of metastatic disease, the nodule size is ≥ 5 mm, and the serum calcitonin level is > 40 pg/mL (Recommendation B).

6. What is the surgical approach in individuals with MTC and distant metastases?

The presence of distant metastases makes a biochemical cure of MTC unlikely. For this reason, the presence of distant metastases should be carefully assessed when the serum calcitonin level is > 400 pg/mL (125125  Franc S, Niccoli-Sire P, Cohen R, Bardet S, Maes B, Murat A, et al. Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma. Clin Endocrinol (Oxf). 2001;55:403-9.,136136  Machens A, Gimm O, Ukkat J, Hinze R, Schneyer U, Dralle H. Improved prediction of calcitonin normalization in medullary thyroid carcinoma patients by quantitative lymph node analysis. Cancer. 2000;88:1909-15.,137137  Tuttle RM, Ganly I. Risk stratification in medullary thyroid cancer: Moving beyond static anatomic staging. Oral Oncol. 2013;49:695-701.) (B/B/D). The surgical treatment of individuals with metastatic disease should focus on local disease control and mainly on the patients’ quality of life (137137  Tuttle RM, Ganly I. Risk stratification in medullary thyroid cancer: Moving beyond static anatomic staging. Oral Oncol. 2013;49:695-701.) (D).

Recommendation 6

The surgical treatment of individuals with advanced local disease or distant metastases should be less aggressive and aimed at local disease control, while preserving the patient’s voice, deglutition, and the parathyroid function and avoiding potential hemorrhagic complications due to the invasion of vascular structures (Recommendation B).

7. What are the indications for mediastinal lymph node dissection in MTC patients?

The mediastinum is divided into a superior portion, which is located above the pericardium, and 3 inferior divisions, the anterior, middle, and posterior. The middle mediastinum contains the heart and pericardium, the anterior mediastinum is bounded anteriorly by the pericardium and posteriorly by the sternum and contains mainly the thymus, and the posterior mediastinum is the area behind the pericardium and contains the esophagus and the thoracic aorta, among other structures (138138  Dralle H, Damm I, Scheumann GF, Kotzerke J, Kupsch E, Geerlings H, et al. Compartment-oriented microdissection of regional lymph nodes in medullary thyroid carcinoma. Surg Today. 1994;24:112-21.) (B). The superior mediastinum contains the thymus and the brachiocephalic artery anteriorly and the trachea and esophagus posteriorly. The superior mediastinum corresponds to level VII of the neck lymph nodes and is included in the dissection of the central compartment (104104  Pelizzo MR, Boschin IM, Bernante P, Toniato A, Piotto A, Pagetta C, et al. Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. Eur J Surg Oncol. 2007;33:493-7.,139139  Machens A, Hauptmann S, Dralle H. Prediction of lateral lymph node metastases in medullary thyroid cancer. Br J Surg. 2008;95:586-91.) (B). Therefore, elective superior mediastinal dissection is usually performed during surgery for MTC via the cervical access. The presence of metastases in lymph nodes of inferior mediastinum, diagnosed by imaging methods (CT or MRI), can be considered as distance metastatic disease, which significantly decreases the chance for cure. Thus, the dissection of this area should only be offered as a palliative treatment in patients with high risk of airway obstruction or bleeding (6464  Ahn JE, Lee JH, Yi JS, Shong YK, Hong SJ, Lee DH, et al. Diagnostic accuracy of CT and ultrasonography for evaluating metastatic cervical lymph nodes in patients with thyroid cancer. World J Surg. 2008;32:1552-8.,121121  Weber T, Schilling T, Frank-Raue K, Colombo-Benkmann M, Hinz U, Ziegler R, et al. Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas. Surgery. 2001;130:1044-9.) (B).

Recommendation 7

Elective superior mediastinal dissection is usually performed during surgery for MTC (Recommendation B). The dissection of the lower mediastinum should be considered only as a palliative treatment in patients with high risk of airway obstruction or bleeding (Recommendation B).

8. What is the required preoperative care for individuals with MTC and suspected or confirmed pheochromocytoma?

In individuals with pheochromocytoma and MTC, adrenalectomy should precede thyroidectomy. An investigation of pheochromocytoma is mandatory in cases with suspected MEN 2 (7272  Machens A, Brauckhoff M, Holzhausen HJ, Thanh PN, Lehnert H, Dralle H. Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2005;90:3999-4003.,7474  Rodriguez JM, Balsalobre M, Ponce JL, Rios A, Torregrosa NM, Tebar J, et al. Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World J Surg. 2008;32:2520-6.,140140  Chen H, Sippel RS, O’Dorisio MS, Vinik AI, Lloyd RV, Pacak K; North American Neuroendocrine Tumor Society (NANETS). The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: Pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010;39775-83.) (B/B/D) and is also indicated in individuals with apparently sporadic MTC that has not yet been subjected to RET molecular testing. Although the occurrence of pheochromocytoma is rather unlikely in these cases, its eventual identification before thyroid surgery is critical, as the complications that arise in undiagnosed cases are severe (7272  Machens A, Brauckhoff M, Holzhausen HJ, Thanh PN, Lehnert H, Dralle H. Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2005;90:3999-4003.,7474  Rodriguez JM, Balsalobre M, Ponce JL, Rios A, Torregrosa NM, Tebar J, et al. Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World J Surg. 2008;32:2520-6.) (B).

A diagnosis of pheochromocytoma is established through the identification of excessive catecholamine production by measuring the plasma and/or urine levels of catecholamines and/or metanephrines. The measurement of plasma metanephrines seems to be most useful in cases of hereditary pheochromocytoma, with sensitivity and specificity rates of 99% and 98%, respectively. When a plasma metanephrine measurement is not available, urine levels might be assessed (7575  Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA. 2002;287:1427-34.,7676  Boyle JG, Davidson DF, Perry CG, Connell JM. Comparison of diagnostic accuracy of urinary free metanephrines, vanillyl mandelic Acid, and catecholamines and plasma catecholamines for diagnosis of pheochromocytoma. J Clin Endocrinol Metab. 2007;92:4602-8.) (B). CT or MRI of the abdomen should be performed to establish the localization of the pheochromocytoma. CT can identify the localization of hereditary adrenal tumors in 76% of evaluated cases (8080  Pomares FJ, Canas R, Rodriguez JM, Hernandez AM, Parrilla P, Tebar FJ. Differences between sporadic and multiple endocrine neoplasia type 2A phaeochromocytoma. Clin Endocrinol (Oxf). 1998;48:195-200.) (B).

Adrenalectomy is indicated for the treatment of pheochromocytoma, preferably by laparoscopy after appropriate preoperative preparation and before surgery for MTC or hyperparathyroidism. The resection of the adrenal medulla (adrenal-sparing surgery), in an attempt to preserve the cortex and avoid adrenal insufficiency, should be considered in cases of bilateral pheochromocytoma (7373  Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612.,140140  Chen H, Sippel RS, O’Dorisio MS, Vinik AI, Lloyd RV, Pacak K; North American Neuroendocrine Tumor Society (NANETS). The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: Pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010;39775-83.) (D). A recent multicenter study involving a large number of patients with MEN 2A-associated pheochromocytoma showed that the recurrence rate in these cases is low (3%), when performed in specialized centers (141141  Castinetti F, Qi XP, Walz MK, Maia AL, Sansó G, Peczkowska M, et al. Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncol. 2014;15:648-55.) (B). Preparation for surgery should be individualized according to patient symptomatology. In general, it is recommended the use of alpha-blockers for 1-2 weeks to reduce systemic vasoconstriction (140140  Chen H, Sippel RS, O’Dorisio MS, Vinik AI, Lloyd RV, Pacak K; North American Neuroendocrine Tumor Society (NANETS). The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: Pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010;39775-83.) (D). Release salt intake and / or saline infusion may also be indicated for the expansion of blood volume (140140  Chen H, Sippel RS, O’Dorisio MS, Vinik AI, Lloyd RV, Pacak K; North American Neuroendocrine Tumor Society (NANETS). The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: Pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010;39775-83.) (D).

Recommendation 8

A proper investigation is needed to confirm or rule out the presence of pheochromocytoma before thyroidectomy (Recommendation B). In individuals with pheochromocytoma and MTC, adrenal surgery should precede thyroidectomy (Recommendation B).

PART III: MTC – FOLLOW-UP

1. Which tests should be performed during the postoperative follow-up of individuals with MTC?

After surgery, patients should be assessed regarding the presence of residual disease, the localization of metastases, and the identification of progressive disease.

Measurements of the serum levels of calcitonin and CEA are of paramount importance during the postoperative follow-ups of individuals with MTC because these biomarkers might indicate the presence and volume of residual disease (142142  Stepanas AV, Samaan NA, Hill CS Jr, Hickey RC. Medullary thyroid carcinoma: importance of serial serum calcitonin measurement. Cancer. 1979;43:825-37.) (B). However, as their nadirs might occur after several weeks (142142  Stepanas AV, Samaan NA, Hill CS Jr, Hickey RC. Medullary thyroid carcinoma: importance of serial serum calcitonin measurement. Cancer. 1979;43:825-37.,143143  Fugazzola L, Pinchera A, Luchetti F, Iacconi P, Miccoli P, Romei C, et al. Disappearance rate of serum calcitonin after total thyroidectomy for medullary thyroid carcinoma. Int J Biol Markers. 1994;9:21-4.) (B/C), measurements should be performed at least 2-3 months after surgery.

The specificities of immunometric assays for calcitonin measurement that use 2 monoclonal or 1 monoclonal and 1 polyclonal antibody are 95-100% (4040  Hasselgren M, Hegedus L, Godballe C, Bonnema SJ. Benefit of measuring basal serum calcitonin to detect medullary thyroid carcinoma in a Danish population with a high prevalence of thyroid nodules. Head Neck. 2010;32:612-8.,4141  Papi G, Corsello SM, Cioni K, Pizzini AM, Corrado S, Carapezzi C, et al. Value of routine measurement of serum calcitonin concentrations in patients with nodular thyroid disease: a multicenter study. J Endocrinol Invest. 2006;29:427-37.) (B/A). To avoid mistakes in the interpretation of results, it should be noted that the absolute values provided by different assays might not be fully comparable. Additionally, the possibility of a hook effect or non-calcitonin-secreting tumors should be considered (false low calcitonin levels) (3838  Leboeuf R, Langlois MF, Martin M, Ahnadi CE, Fink GD. “Hook effect” in calcitonin immunoradiometric assay in patients with metastatic medullary thyroid carcinoma: case report and review of the literature. J Clin Endocrinol Metab. 2006;91:361-4.,3939  Dora JM, Canalli MH, Capp C, Punales MK, Vieira JG, Maia AL. Normal perioperative serum calcitonin levels in patients with advanced medullary thyroid carcinoma: case report and review of the literature. Thyroid. 2008;18:895-9.) (C).

The calcitonin levels might decrease from 24 hours to 4 weeks after surgery, but this could also occur several months later in some cases (142142  Stepanas AV, Samaan NA, Hill CS Jr, Hickey RC. Medullary thyroid carcinoma: importance of serial serum calcitonin measurement. Cancer. 1979;43:825-37.,144144  Tisell LE, Dilley WG, Wells SA Jr. Progression of postoperative residual medullary thyroid carcinoma as monitored by plasma calcitonin levels. Surgery. 1996;119:34-9.,145145  Ismailov SI, Piulatova NR. Postoperative calcitonin study in medullary thyroid carcinoma. Endocr Relat Cancer. 2004;11:357-63.) (B). Persistently high calcitonin levels might be found in patients with kidney failure or liver cirrhosis and MTC, due to an increase in the hormone half-life caused by decline of the renal or hepatic function, thus requiring a differential diagnosis with an actual increase in secretion due to a persistent thyroid neoplasm (146146  Henriksen JH, Schifter S, Moller S, Bendtsen F. Increased circulating calcitonin in cirrhosis. Relation to severity of disease and calcitonin gene-related peptide. Metabolism. 2000;49:47-52.,147147  Austin LA, Heath H 3rd. Calcitonin: physiology and pathophysiology. N Engl J Med. 1981;304:269-78.) (C/D).

In most individuals with sporadic MTC, the calcitonin levels tend to remain high due to residual disease. The likelihood of attaining undetectable calcitonin levels is 83-95% in individuals without lymph node metastases who were subjected to thyroidectomy and neck dissection, but the frequency decreases to 21-30% when neck lymph node metastases are present (9 Scollo C, Baudin E, Travagli JP, Caillou B, Bellon N, Leboulleux S, et al. Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2003;88:2070-5.,121121  Weber T, Schilling T, Frank-Raue K, Colombo-Benkmann M, Hinz U, Ziegler R, et al. Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas. Surgery. 2001;130:1044-9.,148148  Dralle H, Damm I, Scheumann GF, Kotzerke J, Kupsch E. Frequency and significance of cervicomediastinal lymph node metastases in medullary thyroid carcinoma: results of a compartment-oriented microdissection method. Henry Ford Hosp Med J. 1992;40:264-7.) (B).

Although also CEA behaves as a marker of MTC, its levels are not always elevated in all patients and do not systematically correlate with the calcitonin levels. The CEA levels might return to normal values after surgery, even in the presence of elevated calcitonin levels; this might be due to the presence of small residual neoplastic foci. In contrast, in individuals with progressive disease, the CEA levels might increase without a corresponding elevation in the calcitonin levels. Increased serum CEA levels are considered to indicate a poor prognosis (149149  Busnardo B, Girelli ME, Simioni N, Nacamulli D, Busetto E. Nonparallel patterns of calcitonin and carcinoembryonic antigen levels in the follow-up of medullary thyroid carcinoma. Cancer. 1984;53:278-85.) (C).

Recommendation 1

Measurements of serum calcitonin and CEA should be performed 2-3 months after surgery (Recommendation B). If normal calcitonin values are observed, these measurements should be repeated 6-12 months later. Persistently calcitonin/CEA levels are suggestive of persistent or recurrent disease. In such cases, an investigation must be continued to establish the extent of disease.

2. Which factors determine the prognosis of individuals with MTC?

The likelihood of attaining a cure for MTC mostly depends on the tumor stage at the time of diagnosis and a full surgical resection. The main factors associated with poor prognosis include an older age at diagnosis, the primary tumor size, the presence of local and distant metastases, the presence of somatic mutations, and the calcitonin doubling time (150150  Miccoli P, Minuto MN, Ugolini C, Molinaro E, Basolo F, Berti P, et al. Clinically unpredictable prognostic factors in the outcome of medullary thyroid cancer. Endocr Relat Cancer. 2007;14:1099-105.

151  Baloch ZW, LiVolsi VA. Prognostic factors in well-differentiated follicular-derived carcinoma and medullary thyroid carcinoma. Thyroid. 2001;11:637-45.
-152152  Gawlik T, d’Amico A, Szpak-Ulczok S, Skoczylas A, Gubała E, ChoraÇz?y A, et al. The prognostic value of tumor markers doubling times in medullary thyroid carcinoma - preliminary report. Thyroid Res. 2010;3:10.) (B).

The most recent data about the 10-year survival rates for MTC are 95.6%, 75.5% and 40% for patients with tumors confined to the thyroid, local and distant metastases, respectively (1212  Roman S, Lin R, Sosa JA. Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer. 2006;107:2134-42.) (B), and are similar to those previously reported (100%, 93%, 71% e 21%, for stages I, II, III e IV, respectively) (153153  Modigliani E, Cohen R, Campos JM, Conte-Devolx B, Maes B, Boneu A, et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d’etude des tumeurs a calcitonine. Clin Endocrinol (Oxf). 1998;48:265-73.) (B). The survival rates are higher, the regional control of disease is better, and the occurrence of distant metastases is less frequent in individuals < 45 years of age (154154  Chow SM, Chan JK, Tiu SC, Choi KL, Tang DL, Law SC. Medullary thyroid carcinoma in Hong Kong Chinese patients. Hong Kong Med J. 2005;11:251-8.) (B). A tumor size < 0.5 cm correlates with the absence of postoperative clinically or laboratory detectable disease (155155  Pillarisetty VG, Katz SC, Ghossein RA, Tuttle RM, Shaha AR. Micromedullary thyroid cancer: how micro is truly micro? Ann Surg Oncol. 2009;16:2875-81.) (B).

Stage T4b tumors and/or the presence of lymph node and/or distant metastases are associated with lower remission and survival rates (156156  Peixoto Callejo I, Americo Brito J, Zagalo CM, Rosa Santos J. Medullary thyroid carcinoma: multivariate analysis of prognostic factors influencing survival. Clin Transl Oncol. 2006;8:435-43.) (B). Additionally, the localization of metastases influences the prognosis; for example, bone metastases are associated with a poorer prognosis, compared to metastases in soft tissues (1111  Girelli ME, Nacamulli D, Pelizzo MR, De Vido D, Mian C, Piccolo M, et al. Medullary thyroid carcinoma: clinical features and long-term follow-up of seventy-eight patients treated between 1969 and 1986. Thyroid. 1998;8:517-23.) (B).

Prophylactic thyroidectomy is indicated in all RET mutation carriers, and minimally invasive surgery might be considered in asymptomatic carriers. The type of RET mutation correlates with the biological behavior of MTC, and therefore identifying the mutation type might facilitate decision-making with respect to the most adequate age for and the extent of surgery (7373  Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612.,9999  Miccoli P, Elisei R, Donatini G, Materazzi G, Berti P. Video-assisted central compartment lymphadenectomy in a patient with a positive RET oncogene: initial experience. Surg Endosc. 2007;21:120-3.) (D/C). The use of prophylactic surgery improves the cure rates (100100  Punales MK, da Rocha AP, Meotti C, Gross JL, Maia AL. Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A. Thyroid. 2008;18:1261-8.) (B). In individuals with hereditary MTC, a palpable thyroid nodule and lymph node metastases at the time of diagnosis are associated with persistent disease (100100  Punales MK, da Rocha AP, Meotti C, Gross JL, Maia AL. Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A. Thyroid. 2008;18:1261-8.) (B).

The calcitonin and CEA levels might remain steadily high for several years or might exhibit rapid and progressive increases. Serial calcitonin and CEA measurements allow a more accurate assessment of the marker levels through calculations of their doubling times (DT); these might be performed with a tool available at the ATA website (http://www.thyroid.org/thyroid-physicians-professionals/calculators/thyroid-cancer-carcinoma/). The calcitonin DT has prognostic value in individuals with MTC, as it correlates with the survival and tumor recurrence rates (157157  Miyauchi A, Onishi T, Morimoto S, Takai S, Matsuzuka F, Kuma K, et al. Relation of doubling time of plasma calcitonin levels to prognosis and recurrence of medullary thyroid carcinoma. Ann Surg. 1984;199:461-6.) (B). A calcitonin DT calculation requires a minimum of 4 measurements at 6-month intervals. The 5 and 10 – year survival rates are 25% and 8%, respectively, when the DT is < 6 months, and 92% and 37%, respectively, when the DT ranges from 6 months to 2 years. The prognosis was found to be even more favorable in individuals with a DT > 2 years (158158  Barbet J, Campion L, Kraeber-Bodere F, Chatal JF. Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. J Clin Endocrinol Metab. 2005;90:6077-84.) (B).

CEA is a less specific marker of MTC, and the comparison of its DT relative to that of calcitonin revealed diverging results. In one study that compared those markers in a multivariate analysis, both markers behaved as independent predictors of survival; however, the calcitonin DT had a better performance (158158  Barbet J, Campion L, Kraeber-Bodere F, Chatal JF. Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. J Clin Endocrinol Metab. 2005;90:6077-84.) (B). In contrast, according to another study, the CEA DT had a greater impact on prognosis (159159  Meijer JA, le Cessie S, van den Hout WB, Kievit J, Schoones JW, Romijn JA, et al. Calcitonin and carcinoembryonic antigen doubling times as prognostic factors in medullary thyroid carcinoma: a structured meta-analysis. Clin Endocrinol (Oxf). 2010;72:534-42.) (B). Those conflicting results notwithstanding, both markers are useful and allow the identification of high-risk individuals. Therefore, when the calcitonin and CEA DTs indicate rapidly progressing disease, a more thorough assessment that includes imaging tests should be considered whenever possible to localize the disease and indicate the proper treatment.

Recently, Tuttle and Ganly (137137  Tuttle RM, Ganly I. Risk stratification in medullary thyroid cancer: Moving beyond static anatomic staging. Oral Oncol. 2013;49:695-701.) (D) formulated a novel approach to the assessment of postoperative MTC progression, consisting of a dynamic risk stratification similar to that developed for well-differentiated thyroid carcinomas (Table 4). An excellent response is defined as undetectable calcitonin levels after adequate surgical treatment, and the likelihood for achieving such responses is greater when the preoperative calcitonin and CEA levels are low, the primary tumor is small, there are no neck metastases, and the disease is in an early stage. Under such conditions, the 5 and 10 – year recurrence rates vary from < 1 – 8.5%, and the survival rates after surgery are 97-99% at 5 years and 95-97% at 10 years (137137  Tuttle RM, Ganly I. Risk stratification in medullary thyroid cancer: Moving beyond static anatomic staging. Oral Oncol. 2013;49:695-701.,160160  Bihan H, Becker KL, Snider RH, Nylen E, Vittaz L, Lauret C, et al. Calcitonin precursor levels in human medullary thyroid carcinoma. Thyroid. 2003;13:819-22.,161161  Walter MA, Meier C, Radimerski T, Iten F, Kranzlin M, Muller-Brand J, et al. Procalcitonin levels predict clinical course and progression-free survival in patients with medullary thyroid cancer. Cancer. 2010;116:31-40.) (D/B/B).

Table 4
Risk stratification system for evaluation of medullary thyroid carcinoma after initial therapy

Incomplete responses are exhibited by 45-70% of the cases and are characterized by evidence of persistent disease after the initial treatment (7373  Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612.,136136  Machens A, Gimm O, Ukkat J, Hinze R, Schneyer U, Dralle H. Improved prediction of calcitonin normalization in medullary thyroid carcinoma patients by quantitative lymph node analysis. Cancer. 2000;88:1909-15.,137137  Tuttle RM, Ganly I. Risk stratification in medullary thyroid cancer: Moving beyond static anatomic staging. Oral Oncol. 2013;49:695-701.,161161  Walter MA, Meier C, Radimerski T, Iten F, Kranzlin M, Muller-Brand J, et al. Procalcitonin levels predict clinical course and progression-free survival in patients with medullary thyroid cancer. Cancer. 2010;116:31-40.) (D/B/D/B). Additionally, the presence of distant metastases after the initial treatment is considered an incomplete response to the initial treatment. The 5 and 10 – year survival rates of individuals with persistently elevated calcitonin levels are 80-86% and 70%, respectively (153153  Modigliani E, Cohen R, Campos JM, Conte-Devolx B, Maes B, Boneu A, et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d’etude des tumeurs a calcitonine. Clin Endocrinol (Oxf). 1998;48:265-73.,161161  Walter MA, Meier C, Radimerski T, Iten F, Kranzlin M, Muller-Brand J, et al. Procalcitonin levels predict clinical course and progression-free survival in patients with medullary thyroid cancer. Cancer. 2010;116:31-40.

162  Cupisti K, Wolf A, Raffel A, Schott M, Miersch D, Yang Q, et al. Long-term clinical and biochemical follow-up in medullary thyroid carcinoma: a single institution’s experience over 20 years. Ann Surg. 2007;246:815-21.
-163163  Rendl G, Manzl M, Hitzl W, Sungler P, Pirich C. Long-term prognosis of medullary thyroid carcinoma. Clin Endocrinol (Oxf). 2008;69:497-505.) (B/A). The cases with unspecific abnormalities on imaging tests, non-normalized tumor marker levels, or no detectable evidence of anatomical and biochemical disease are classified as indeterminate responses (137137  Tuttle RM, Ganly I. Risk stratification in medullary thyroid cancer: Moving beyond static anatomic staging. Oral Oncol. 2013;49:695-701.,164164  Tuttle RM, Tala H, Shah J, Leboeuf R, Ghossein R, Gonen M, et al. Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid. 2010;20:1341-9.) (D/B).

Recommendation 2

The main prognostic factors of survival in individuals with MTC are age, the tumor stage at the time of diagnosis, and the calcitonin and CEA doubling times (Recommendation B). In individuals with hereditary MTC, the main prognostic factor of cure and survival is the performance of a prophylactic thyroidectomy following the identification of RET gene mutations (Recommendation B).

3. Which tests should be performed in individuals with persistently detectable calcitonin levels after initial surgery?

The postoperative serum calcitonin levels determine the strategies used for further assessments. Calcitonin levels < 150 pg/mL correlate with the presence of locoregional disease, but the likelihood of distant metastases is low or they are few in number (6868  Yen TW, Shapiro SE, Gagel RF, Sherman SI, Lee JE, Evans DB. Medullary thyroid carcinoma: results of a standardized surgical approach in a contemporary series of 80 consecutive patients. Surgery. 2003;134:890-9.,165165  Laure Giraudet A, Al Ghulzan A, Auperin A, Leboulleux S, Chehboun A, Troalen F, et al. Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times. Eur J Endocrinol. 2008;158:239-46.) (B).

The initial assessment test is neck US. The rate of local MTC relapse might be as high as 58% (6262  Kouvaraki MA, Shapiro SE, Fornage BD, Edeiken-Monro BS, Sherman SI, Vassilopoulou-Sellin R, et al. Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer. Surgery. 2003;134:946-54.,6868  Yen TW, Shapiro SE, Gagel RF, Sherman SI, Lee JE, Evans DB. Medullary thyroid carcinoma: results of a standardized surgical approach in a contemporary series of 80 consecutive patients. Surgery. 2003;134:890-9.,166166  Lundgren CI, Delbridg L, Learoyd D, Robinson B. Surgical approach to medullary thyroid cancer. Arq Bras Endocrinol Metabol. 2007;51:818-24.) (B/B/D). The sensitivity of neck US for diagnosing locoregional metastases is 97%, compared to 72% with CT and 55% with positron emission tomography (PET)-CT (1010  Giraudet AL, Vanel D, Leboulleux S, Auperin A, Dromain C, Chami L, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 2007;92:4185-90.) (B). When suspected metastatic lymph nodes are found, a puncture biopsy might help to elucidate the diagnosis, and the sensitivity and specificity of this test increase when calcitonin is measured in the washout fluid (2222  Boi F, Maurelli I, Pinna G, Atzeni F, Piga M, Lai ML, et al. Calcitonin measurement in wash-out fluid from fine needle aspiration of neck masses in patients with primary and metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab. 2007;92:2115-8.) (B). CT can identify 100% of the cases with mediastinal lymph node involvement, versus 65% with PET-CT (1010  Giraudet AL, Vanel D, Leboulleux S, Auperin A, Dromain C, Chami L, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 2007;92:4185-90.) (B).

The presence of distant metastases might be investigated with CT of the neck and/or chest, MRI, bone scintigraphy, and [18F]-fluorodeoxyglucose (18F-FDG) PET-CT. The sensitivities of these tests for detecting metastatic disease vary from 50-80%. The likelihood of identifying metastatic disease is lower in individuals with discrete calcitonin elevation (1010  Giraudet AL, Vanel D, Leboulleux S, Auperin A, Dromain C, Chami L, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 2007;92:4185-90.,167167  Mirallie E, Vuillez JP, Bardet S, Frampas E, Dupas B, Ferrer L, et al. High frequency of bone/bone marrow involvement in advanced medullary thyroid cancer. J Clin Endocrinol Metab. 2005;90:779-88.

168  Koopmans KP, de Groot JW, Plukker JT, de Vries EG, Kema IP, Sluiter WJ, et al. 18F-dihydroxyphenylalanine PET in patients with biochemical evidence of medullary thyroid cancer: relation to tumor differentiation. J Nucl Med. 2008;49:524-31.

169  Szakall S Jr, Esik O, Bajzik G, Repa I, Dabasi G, Sinkovics I, et al. 18F-FDG PET detection of lymph node metastases in medullary thyroid carcinoma. J Nucl Med. 2002;43:66-71.
-170170  Diehl M, Risse JH, Brandt-Mainz K, Dietlein M, Bohuslavizki KH, Matheja P, et al. Fluorine-18 fluorodeoxyglucose positron emission tomography in medullary thyroid cancer: results of a multicentre study. Eur J Nucl Med. 2001;28):1671-6.) (B), but high when the calcitonin levels exceed 150 pg/mL (165165  Laure Giraudet A, Al Ghulzan A, Auperin A, Leboulleux S, Chehboun A, Troalen F, et al. Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times. Eur J Endocrinol. 2008;158:239-46.) (B).

The median calcitonin levels in individuals with 1 and 2-4 metastatic sites are 1,510 pg/mL and 18,450 pg/mL, respectively (165165  Laure Giraudet A, Al Ghulzan A, Auperin A, Leboulleux S, Chehboun A, Troalen F, et al. Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times. Eur J Endocrinol. 2008;158:239-46.) (B). The most frequent sites of distant metastasis are the liver (49%), bones (45%), and lungs (35%) (1010  Giraudet AL, Vanel D, Leboulleux S, Auperin A, Dromain C, Chami L, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 2007;92:4185-90.) (B). The sensitivities of CT and US for diagnosing liver metastases are similar (90% and 85%, respectively), but lower than that of MRI (100%) (1010  Giraudet AL, Vanel D, Leboulleux S, Auperin A, Dromain C, Chami L, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 2007;92:4185-90.) (B). Bone scintigraphy is indicated for investigating low-mechanical risk lesions (ribs, sternum, clavicles, and skull), and axial skeleton MRI is indicated for high-mechanical risk lesions (spine, pelvic bones, and long bones). CT is the most accurate method for diagnosing lung metastases. Therefore, the best test combination for detecting distant metastases includes chest CT, liver MRI, and bone scintigraphy and/or axial skeleton MRI (1010  Giraudet AL, Vanel D, Leboulleux S, Auperin A, Dromain C, Chami L, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 2007;92:4185-90.) (B).

Experiences with the use of [18F]-dihydroxyphenylalanine (18F-DOPA) PET in metastatic MTC remain limited. This method has a sensitivity rate of 63% and might be used to investigate metastases in cases of slowly progressive MTC (168168  Koopmans KP, de Groot JW, Plukker JT, de Vries EG, Kema IP, Sluiter WJ, et al. 18F-dihydroxyphenylalanine PET in patients with biochemical evidence of medullary thyroid cancer: relation to tumor differentiation. J Nucl Med. 2008;49:524-31.,171171  Beuthien-Baumann B, Strumpf A, Zessin J, Bredow J, Kotzerke J. Diagnostic impact of PET with 18F-FDG, 18F-DOPA and 3-O-methyl-6-[18F]fluoro-DOPA in recurrent or metastatic medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging. 2007;34:1604-9.) (B). Metaiodobenzylguanidine (MIBG) scintigraphy might be useful in some cases, while somatostatin receptor scintigraphy is an additional option when the serum calcitonin levels are > 800 pg/mL (172172  Faggiano A, Grimaldi F, Pezzullo L, Chiofalo MG, Caraco C, Mozzillo N, et al. Secretive and proliferative tumor profile helps to select the best imaging technique to identify postoperative persistent or relapsing medullary thyroid cancer. Endocr Relat Cancer. 2009;16:225-31.) (B).

In individuals with high calcitonin levels and negative imaging tests, 18F-FDG PET-CT had sensitivity, specificity, and diagnostic accuracy rates of 88%, 84.6%, and 87%, respectively, for the detection of occult recurrences of MTC (173173  Gomez-Camarero P, Ortiz-de Tena A, Borrego-Dorado I, Vazquez-Albertino RJ, Navarro-Gonzalez E, Ruiz-Franco-Baux JV, et al. [Evaluation of efficacy and clinical impact of 18F-FDG-PET in the diagnosis of recurrent medullary thyroid cancer with increased calcitonin and negative imaging test]. Rev Esp Med Nucl Imagen Mol. 2012;31:261-6.) (B). In a comparison of 18F-FDG, 18F-DOPA, and 68Ga-somatostatin analogue PET-CT in individuals with recurrent MTC, the metastatic lesion detection rates were 28%, 85%, and 20%, respectively. According to those data, 18F-DOPA PET-CT seems to be the most useful method for detecting MTC recurrences in individuals with elevated serum calcitonin levels (174174  Treglia G, Castaldi P, Villani MF, Perotti G, de Waure C, Filice A, et al. Comparison of 18F-DOPA, 18F-FDG and 68Ga-somatostatin analogue PET/CT in patients with recurrent medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging. 2012;39:569-80.) (B). However, other studies showed no significant differences between PET 18F-DOPA and 18F-FDG in the same population (175175  Naswa N, Sharma P, Suman Kc S, Lata S, Kumar R, Malhotra A, et al. Prospective evaluation of 68Ga-DOTA-NOC PET-CT in patients with recurrent medullary thyroid carcinoma: comparison with 18F-FDG PET-CT. Nucl Med Commun. 2012 33:766-74.) (B).

Recommendation 3 (Flowchart 2)

Basal calcitonin levels < 150 pg/mL are associated with the presence of locoregional disease, and neck US should be the first test used in the assessment (Recommendation B). The likelihood of detecting distant metastases is higher among patients with calcitonin levels > 150 pg/mL. In such cases, chest CT, abdominal MRI, and bone scintigraphy should be performed to establish the presence of mediastinal and lung, liver, and bone metastases, respectively (Recommendation B).

Flowchart 2
. Evaluation of patients with medullary thyroid carcinoma post-surgery.

4. Which tests should be performed during the follow-up of individuals with undetectable calcitonin levels after surgery?

Serum calcitonin is the most sensitive marker of residual MTC after surgery. According to some studies, the calcitonin levels are below the threshold of detection in 100% of the individuals subjected to total thyroidectomy (176176  Engelbach M, Gorges R, Forst T, Pfutzner A, Dawood R, Heerdt S, et al. Improved diagnostic methods in the follow-up of medullary thyroid carcinoma by highly specific calcitonin measurements. J Clin Endocrinol Metab. 2000;85:1890-4.) (B). The likelihood of residual/recurrent disease in individuals with undetectable basal and post-pentagastrin stimulation calcitonin levels after surgery was reported to be approximately 3% (125125  Franc S, Niccoli-Sire P, Cohen R, Bardet S, Maes B, Murat A, et al. Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma. Clin Endocrinol (Oxf). 2001;55:403-9.) (B).

The likelihood that calcitonin levels will become undetectable after total thyroidectomy is 95% in individuals with thyroid gland-restricted disease. The presence of neck metastases reduces the likelihood that calcitonin will return to normal values to 30% (9 Scollo C, Baudin E, Travagli JP, Caillou B, Bellon N, Leboulleux S, et al. Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2003;88:2070-5.). Although the average time for the recurrence of MTC is 3.2 ± 2.2 years, the calcitonin levels should be measured every 6-12 months for a still-undefined period of time, including after they have become undetectable after surgery, due to the risk of disease relapse (125125  Franc S, Niccoli-Sire P, Cohen R, Bardet S, Maes B, Murat A, et al. Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma. Clin Endocrinol (Oxf). 2001;55:403-9.) (B).

It is worth observing that a few cases of individuals with advanced MTC and normal serum calcitonin levels were reported (3939  Dora JM, Canalli MH, Capp C, Punales MK, Vieira JG, Maia AL. Normal perioperative serum calcitonin levels in patients with advanced medullary thyroid carcinoma: case report and review of the literature. Thyroid. 2008;18:895-9.,177177  Redding AH, Levine SN, Fowler MR. Normal preoperative calcitonin levels do not always exclude medullary thyroid carcinoma in patients with large palpable thyroid masses. Thyroid. 2000;10:919-22.) (C). Those patients’ follow-ups should include imaging modalities. Measurements of the calcitonin levels in the FNAB washout fluid might facilitate the proper diagnoses of suspected MTC metastatic lesions (2222  Boi F, Maurelli I, Pinna G, Atzeni F, Piga M, Lai ML, et al. Calcitonin measurement in wash-out fluid from fine needle aspiration of neck masses in patients with primary and metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab. 2007;92:2115-8.,2323  Siqueira D, Rocha AP, Punales MK, Maia AL. Identification of occult metastases of medullary thyroid carcinoma by calcitonin measurement in washout fluid from fine needle aspiration of cervical lymph node. Arq Bras Endocrinol Metabol. 2009;53:479-81.) (B/C).

Recommendation 4

Measurements of serum calcitonin levels should be performed every 6-12 months for a still-undefined period of time in individuals with undetectable levels after surgery due to the risk of disease relapse (Recommendation B). Measurements of the calcitonin level in the FNAB washout fluid might facilitate the diagnoses of suspected lesions (Recommendation B).

5. When is the pentagastrin or calcium stimulation test for calcitonin indicated in patients already subjected to surgery?

In some individuals with undetectable basal calcitonin levels, pentagastrin and/or calcium stimulation might increase these levels, thus indicating the presence of residual disease. However, the localization of residual disease is very difficult to establish with imaging methods in the vast majority of such cases (134134  Skinner MA, Moley JA, Dilley WG, Owzar K, Debenedetti MK, Wells SA Jr. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med. 2005;353:1105-13.,176176  Engelbach M, Gorges R, Forst T, Pfutzner A, Dawood R, Heerdt S, et al. Improved diagnostic methods in the follow-up of medullary thyroid carcinoma by highly specific calcitonin measurements. J Clin Endocrinol Metab. 2000;85:1890-4.,178178  Wells SA Jr, Baylin SB, Linehan WM, Farrell RE, Cox EB, Cooper CW. Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg. 1978;188:39-41.) (B/B/C). Further disadvantages associated with these stimulation tests are their costs, side effects, and the unavailability of pentagastrin in Brazil.

Recommendation 5

The pentagastrin/calcium stimulation test is not indicated for the follow-up of individuals with undetectable basal serum calcitonin, as positive results denote residual diseases that are difficult to locate with imaging methods (Recommendation B).

6. What should comprise the management of patients with persistently detectable calcitonin levels after primary surgery?

Curative reoperation (to achieve undetectable serum calcitonin levels) is indicated in individuals who exhibit evidence of persistent disease due to an incomplete primary surgery or a disease recurrence in the neck. The presence of inoperable distant metastases should be ruled out before a cervical reoperation is considered. Surgery might also have palliative indications in cases with the risk of compression or invasion of the trachea or the great vessels (179179  Randolph GW, Maniar D. Medullary carcinoma of the thyroid. Cancer Control. 2000;7:253-61.) (D). Expectant management, including periodical clinical and laboratory assessments, is indicated in cases of indolent disease that have already been subjected to appropriate surgical treatments (179179  Randolph GW, Maniar D. Medullary carcinoma of the thyroid. Cancer Control. 2000;7:253-61.) (D). Follow-up measurements of serum calcitonin in individuals with MTC might determine the later management.

Discrete increases in the calcitonin levels (< 150 pg/mL) at 2-3 months after surgery are associated with locoregional disease or small distant metastases in most cases (6868  Yen TW, Shapiro SE, Gagel RF, Sherman SI, Lee JE, Evans DB. Medullary thyroid carcinoma: results of a standardized surgical approach in a contemporary series of 80 consecutive patients. Surgery. 2003;134:890-9.,165165  Laure Giraudet A, Al Ghulzan A, Auperin A, Leboulleux S, Chehboun A, Troalen F, et al. Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times. Eur J Endocrinol. 2008;158:239-46.) (B). When residual or recurrent disease is detected in the neck, surgical reintervention should be considered. The rates of calcitonin normalization after cervical reoperation vary from 16-38% (180180  Gimm O, Dralle H. Reoperation in metastasizing medullary thyroid carcinoma: is a tumor stage-oriented approach justified? Surgery. 1997;122:1124-30.

181  Kebebew E, Kikuchi S, Duh QY, Clark OH. Long-term results of reoperation and localizing studies in patients with persistent or recurrent medullary thyroid cancer. Arch Surg. 2000;135:895-901.

182  Tisell LE, Hansson G, Jansson S, Salander H. Reoperation in the treatment of asymptomatic metastasizing medullary thyroid carcinoma. Surgery. 1986;99:60-6.

183  Moley JF, Debenedetti MK, Dilley WG, Tisell LE, Wells SA. Surgical management of patients with persistent or recurrent medullary thyroid cancer. J Intern Med. 1998;243:521-6.
-184184  Fialkowski E, DeBenedetti M, Moley J. Long-term outcome of reoperations for medullary thyroid carcinoma. World J Surg. 2008;32:754-65.) (B). A retrospective study found that reoperation allowed the identification of residual disease in the lateral lymph nodes in 64% of cases, in the central compartment in 22%, and in the anterior mediastinum in 14% of cases. The serum calcitonin levels returned to normal in only 6% of the investigated individuals; however, the remainder of the sample exhibited 50% reductions or stabilization of the calcitonin levels (181181  Kebebew E, Kikuchi S, Duh QY, Clark OH. Long-term results of reoperation and localizing studies in patients with persistent or recurrent medullary thyroid cancer. Arch Surg. 2000;135:895-901.) (B). Another study followed up individuals who were subjected to reoperation for MTC over a period of 8-10 years and found calcitonin levels < 10 pg/mL in 26% of the participants and < 100 pg/mL in an additional 20.4% of patients. Disease could not be detected with imaging methods in any of those individuals (184184  Fialkowski E, DeBenedetti M, Moley J. Long-term outcome of reoperations for medullary thyroid carcinoma. World J Surg. 2008;32:754-65.) (B).

Although reoperation might reduce the disease progression in selected individuals, a biological cure of MTC is seldom achieved in such cases. For that reason, the surgical approach to recurrent or persistent MTC in individuals with no or minimal distant metastases should include dissection of the affected central (level VI) or lateral (levels IIA, III, IV, and V) compartments. Expectant management is recommended for cases in which the anatomical localization of the metastases cannot be established (179179  Randolph GW, Maniar D. Medullary carcinoma of the thyroid. Cancer Control. 2000;7:253-61.).

Significantly elevated calcitonin levels (> 150 pg/mL) at 2-3 months after surgery are usually associated with the presence of distant metastases, and the higher the calcitonin level, the higher the likelihood of identifying the lesion localization (185185  van Heerden JA, Grant CS, Gharib H, Hay ID, Ilstrup DM. Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg. 1990;212:395-400.) (B). As a rule, the management of individuals with calcitonin levels > 150 pg/mL is similar to that of patients with lower levels (186186  Moley JF, Fialkowski EA. Evidence-based approach to the management of sporadic medullary thyroid carcinoma. World J Surg. 2007;31:946-56.) (D).

The therapeutic strategy for individuals with locoregional and distant metastases should be decided on an individual basis, while considering the indolent course of MTC and the morbidity associated with the available treatments. The presence of neck lymph nodes < 1 cm and asymptomatic distant metastases does not suggest a need for intervention, as treatment has not proven beneficial in such cases. Possible therapeutic options include surgery, percutaneous interventions, liver metastasis embolization, radiotherapy, and tyrosine-kinase inhibitors (187187  Fialkowski EA, Moley JF. Current approaches to medullary thyroid carcinoma, sporadic and familial. J Surg Oncol. 2006;94:737-47.) (D). It is worth observing that the likelihood of a cure in individuals with distant metastases is minimal. The relative risks and benefits of any procedure should be carefully assessed when deciding whether palliative therapy or watchful waiting is indicated.

Recommendation 6

Serum calcitonin is the most relevant biomarker for the follow up individuals with MTC (Recommendation B). Discrete increases in the calcitonin levels (< 150 pg/mL) usually denote the presence of locoregional disease (Recommendation B). More substantial elevations (> 150 pg/mL) are suggestive of distant metastases (Recommendation B). The best methods for investigating metastases are US for the neck, CT for the chest, MRI for the liver, and bone scintigraphy and/or axial skeleton MRI for the bones (Recommendation B).

A new surgical procedure should be considered in presence of residual or recurrent local disease (Recommendation B). In patients with distant metastases, the treatment strategy should be individualized, taking into consideration the indolent course of CMT and the morbidity associated with available therapies (Recommendation D).

7. What is the appropriate management for individuals with increased calcitonin levels and negative imaging tests?

Individuals with detectable calcitonin levels after surgery should be assessed with imaging methods to locate the disease site. When imaging tests fail to identify the disease foci, the patients should be subjected to periodical assessments at intervals determined by the calcitonin and CEA DT, as these are markers of disease progression (158158  Barbet J, Campion L, Kraeber-Bodere F, Chatal JF. Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. J Clin Endocrinol Metab. 2005;90:6077-84.,165165  Laure Giraudet A, Al Ghulzan A, Auperin A, Leboulleux S, Chehboun A, Troalen F, et al. Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times. Eur J Endocrinol. 2008;158:239-46.) (B). To calculate the DTs, the serum calcitonin and CEA levels should be measured every 6 months, and the ideal interval for assessments of individuals with MTC corresponds to one-fourth of the DT or each year, whichever is shorter.

Recommendation 7

Individuals with elevated serum calcitonin levels and negative imaging tests should be assessed at least every 6 months, and these assessments should include measurements of the calcitonin and CEA levels to calculate their DTs (Recommendation B).

8. What should comprise the treatment of individuals with MTC and distant metastases?

The following questions should be considered during decision-making, with respect to the best management of individuals with metastatic MTC:

  • Is the patient symptomatic or asymptomatic?

  • Where are the metastases located?

  • Are there lesions that require intervention due to imminent risk or associated symptoms (e.g., brain lesions, painful bone lesions or those with a risk of fracture, or chest pain and the risk of bronchial obstruction)?

  • Is the locoregional disease controlled?

  • What is the speed of metastatic disease progression?

The treatment of distant metastases is indicated in cases associated with an imminent risk of serious complications such as brain metastases, lesions that cause spinal cord compression or airway affection, hormone-secreting metastases, or bone metastases that exhibit an active or imminent risk of fracture. Expectant management might be indicated in asymptomatic individuals who exhibit small indolent metastases. Patients with rapidly progressive disease, as evidenced by imaging or laboratory testing, are candidates for systemic novel drug treatment.

The disease progression speed might be assessed from the calcitonin and CEA DTs or imaging results that have been interpreted according to the Response Evaluation Criteria In Solid Tumors (RECIST), in which increases > 20% in the sum of the lesions’ diameters are classified as progressive disease (158158  Barbet J, Campion L, Kraeber-Bodere F, Chatal JF. Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. J Clin Endocrinol Metab. 2005;90:6077-84.,165165  Laure Giraudet A, Al Ghulzan A, Auperin A, Leboulleux S, Chehboun A, Troalen F, et al. Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times. Eur J Endocrinol. 2008;158:239-46.,188188  Pellegriti G, Leboulleux S, Baudin E, Bellon N, Scollo C, Travagli JP, et al. Long-term outcome of medullary thyroid carcinoma in patients with normal postoperative medical imaging. Br J Cancer. 2003;88:1537-42.) (B).

Recommendation 8

Systemic treatment should be considered for symptomatic individuals and/or those with documented significant disease progression (according to radiological methods and/or a calcitonin or CEA DT < 6 months) (Recommendation B).

9. What should comprise the treatment of individuals with hormone-secreting metastases?

The ectopic production of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) and the secretion of VIP, insulin, and glucagon were described in individuals with MTC (5252  Said SI. Evidence for secretion of vasoactive intestinal peptide by tumours of pancreas, adrenal medulla, thyroid and lung: support for the unifying APUD concept. Clin Endocrinol (Oxf). 1976;5 Suppl:201S-4S.,5353  Holm R, Sobrinho-Simoes M, Nesland JM, Gould VE, Johannessen JV. Medullary carcinoma of the thyroid gland: an immunocytochemical study. Ultrastruct Pathol. 1985;8:25-41.,189189  Hanna FW, Ardill JE, Johnston CF, Cunningham RT, Curry WJ, Russell CF, et al. Regulatory peptides and other neuroendocrine markers in medullary carcinoma of the thyroid. J Endocrinol. 1997;152:275-81.,190190  Jenkins PJ, Satta MA, Simmgen M, Drake WM, Williamson C, Lowe DG, et al. Metastatic parathyroid carcinoma in the MEN2A syndrome. Clin Endocrinol (Oxf). 1997;47:747-51.) (B/B/D/C).

Diarrhea might appear due to increased intestinal motility (191191  Rambaud JC, Jian R, Flourie B, Hautefeuille M, Salmeron M, Thuillier F, et al. Pathophysiological study of diarrhoea in a patient with medullary thyroid carcinoma. Evidence against a secretory mechanism and for the role of shortened colonic transit time. Gut. 1988;29:537-43.) (C) or the hypersecretion of calcitonin and/or VIP (5252  Said SI. Evidence for secretion of vasoactive intestinal peptide by tumours of pancreas, adrenal medulla, thyroid and lung: support for the unifying APUD concept. Clin Endocrinol (Oxf). 1976;5 Suppl:201S-4S.,192192  Cox TM, Fagan EA, Hillyard CJ, Allison DJ, Chadwick VS. Role of calcitonin in diarrhoea associated with medullary carcinoma of the thyroid. Gut. 1979;20:629-33.) (B/C). According to recommendations, treatment should initially include antimotility agents (loperamide or codeine). Further options for unsuccessful cases include the use of somatostatin analogues (193193  Vainas I, Koussis C, Pazaitou-Panayiotou K, Drimonitis A, Chrisoulidou A, Iakovou I, et al. Somatostatin receptor expression in vivo and response to somatostatin analog therapy with or without other antineoplastic treatments in advanced medullary thyroid carcinoma. J Exp Clin Cancer Res. 2004;23:549-59.

194  Zatelli MC, Piccin D, Tagliati F, Bottoni A, Luchin A, Vignali C, et al. Selective activation of somatostatin receptor subtypes differentially modulates secretion and viability in human medullary thyroid carcinoma primary cultures: potential clinical perspectives. J Clin Endocrinol Metab. 2006;91:2218-24.
-195195  Mahler C, Verhelst J, de Longueville M, Harris A. Long-term treatment of metastatic medullary thyroid carcinoma with the somatostatin analogue octreotide. Clin Endocrinol (Oxf). 1990;33:261-9.) (B) and the selective resection or arterial chemoembolization of liver metastases to reduce the hypercalcitonemia caused by those lesions (196196  Lorenz K, Brauckhoff M, Behrmann C, Sekulla C, Ukkat J, Brauckhoff K, et al. Selective arterial chemoembolization for hepatic metastases from medullary thyroid carcinoma. Surgery. 2005;138:986-93.,197197  Fromigue J, De Baere T, Baudin E, Dromain C, Leboulleux S, Schlumberger M. Chemoembolization for liver metastases from medullary thyroid carcinoma. J Clin Endocrinol Metab. 2006;91:2496-9.) (B/C).

MTC comprises 2-6% of ectopic Cushing’s syndrome cases (198198  Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK. Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005;90:4955-62.,199199  Smallridge RC, Bourne K, Pearson BW, Van Heerden JA, Carpenter PC, Young WF. Cushing’s syndrome due to medullary thyroid carcinoma: diagnosis by proopiomelanocortin messenger ribonucleic acid in situ hybridization. J Clin Endocrinol Metab. 2003;88:4565-8.) (B/C), and treatment might include surgery or chemoembolization for liver metastases. Additionally, adrenolytic drugs (ketoconazole, milotane, or metyrapone) might be used, while bilateral adrenalectomy is indicated in uncontrolled cases (198198  Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK. Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005;90:4955-62.

199  Smallridge RC, Bourne K, Pearson BW, Van Heerden JA, Carpenter PC, Young WF. Cushing’s syndrome due to medullary thyroid carcinoma: diagnosis by proopiomelanocortin messenger ribonucleic acid in situ hybridization. J Clin Endocrinol Metab. 2003;88:4565-8.
-200200  Winquist EW, Laskey J, Crump M, Khamsi F, Shepherd FA. Ketoconazole in the management of paraneoplastic Cushing’s syndrome secondary to ectopic adrenocorticotropin production. J Clin Oncol. 1995;13:157-64.) (B/C/C). Recently, it has been reported a sorafenib-induced reduction of cortisol and ACTH levels, associated with dramatic clinical improvement, in a patient with advanced MTC and ectopic ACTH syndrome (201201  Barroso-Sousa R, Lerario AM, Evangelista J, Papadia C, Lourenço DM Jr, Lin CS, et al. Complete resolution of hypercortisolism with sorafenib in a patient with advanced medullary thyroid carcinoma and ectopic ACTH (adrenocorticotropic hormone) syndrome. Thyroid. 2014;24(6):1062-6.) (C).

Recommendation 9

Advanced MTC metastatic disease might be attended by systemic hormonal changes secondary to the increased calcitonin levels and/or the ectopic production of some specific hormones. Treatment should be planned on an individual basis according to the clinical manifestations of the existing dysfunction (Recommendation B).

10. What are the indications for chemotherapy and/or radiotherapy in the management of individuals with metastatic MTC?

Radiotherapy

The role of radiotherapy in the treatment of MTC is rather limited (202202  Terezakis SA, Lee KS, Ghossein RA, Rivera M, Tuttle RM, Wolden SL, et al. Role of external beam radiotherapy in patients with advanced or recurrent nonanaplastic thyroid cancer: Memorial Sloan-kettering Cancer Center experience. Int J Radiat Oncol Biol Phys. 2009;73:795-801.

203  Schwartz DL, Rana V, Shaw S, Yazbeck C, Ang KK, Morrison WH, et al. Postoperative radiotherapy for advanced medullary thyroid cancer--local disease control in the modern era. Head Neck. 2008;30:883-8.
-204204  Brierley J, Sherman E. The role of external beam radiation and targeted therapy in thyroid cancer. Semin Radiat Oncol. 2012;22(3):254-62.) (B/B/D). In individuals at a high risk of local recurrence (locally invasive tumors, microscopic residual disease, and neck lymph node involvement), radiotherapy was shown to reduce the local recurrence rate in 86% of patients at a 10 – year follow-up (205205  Brierley J, Tsang R, Simpson WJ, Gospodarowicz M, Sutcliffe S, Panzarella T. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid. 1996;(6):305-10.) (B).

The indication for radiotherapy in systemic metastatic disease is restricted to the palliative treatment of painful bone metastases or those at risk of fracture, as described for bone metastases secondary to other types of tumors (206206  Hartsell WF, Scott CB, Bruner DW, Scarantino CW, Ivker RA, Roach M 3rd, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst. 2005;97(11):798-804.) (B), and to the treatment of hemoptysis or airway obstruction in individuals with extensive mediastinal and/or lung involvement (204204  Brierley J, Sherman E. The role of external beam radiation and targeted therapy in thyroid cancer. Semin Radiat Oncol. 2012;22(3):254-62.,207207  Masala S, Manenti G, Roselli M, Mammucari M, Bartolucci DA, Formica V, et al. Percutaneous combined therapy for painful sternal metastases: a radiofrequency thermal ablation (RFTA) and cementoplasty protocol. Anticancer Res. 2007;27:4259-62.) (D/C).

Systemic chemotherapy

The results of studies of single or combined chemotherapy agents have not been satisfactory. No phase III studies with large numbers of patients have been conducted. A combination of doxorubicin, dacarbazine, and streptozocin induced partial responses in 15% of a sample of individuals with MTC (208208  Nocera M, Baudin E, Pellegriti G, Cailleux AF, Mechelany-Corone C, Schlumberger M. Treatment of advanced medullary thyroid cancer with an alternating combination of doxorubicin-streptozocin and 5 FU-dacarbazine. Groupe d’Etude des Tumeurs a Calcitonine (GETC). Br J Cancer. 2000;83:715-8.,209209  Frame J, Kelsen D, Kemeny N, Cheng E, Niedzwiecki D, Heelan R, et al. A phase II trial of streptozotocin and adriamycin in advanced APUD tumors. Am J Clin Oncol. 1988;11(4):490-5.) (B). Additionally, the results were limited in studies that used cyclophosphamide, vincristine, cisplatin, and bleomycin (208208  Nocera M, Baudin E, Pellegriti G, Cailleux AF, Mechelany-Corone C, Schlumberger M. Treatment of advanced medullary thyroid cancer with an alternating combination of doxorubicin-streptozocin and 5 FU-dacarbazine. Groupe d’Etude des Tumeurs a Calcitonine (GETC). Br J Cancer. 2000;83:715-8.,210210  Bajetta E, Rimassa L, Carnaghi C, Seregni E, Ferrari L, Di Bartolomeo M, et al. 5-Fluorouracil, dacarbazine, and epirubicin in the treatment of patients with neuroendocrine tumors. Cancer. 1998;15:83(2):372-8.

211  De Besi P, Busnardo B, Toso S, Girelli ME, Nacamulli D, Simioni N, et al. Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer. J Endocrinol Invest. 1991;14:475-80.
-212212  Schlumberger M, Abdelmoumene N, Delisle MJ, Couette JE. Treatment of advanced medullary thyroid cancer with an alternating combination of 5 FU-streptozocin and 5 FU-dacarbazine. The Groupe d’Etude des Tumeurs a Calcitonine (GETC). Br J Cancer. 1995;71:363-5.) (B). Therefore, as conventional chemotherapy has not been effective, it is exclusively recommended for selected individuals with rapidly progressive metastatic disease.

Recommendation 10

Radiotherapy should be considered for local disease control (Recommendation B), the palliative treatment of painful bone metastases or those at risk of fracture (Recommendation B), and for the treatment of hemoptysis or airway obstruction in individuals with extensive mediastinal and/or lung involvement (Recommendation D). The effects of conventional chemotherapy are limited, and thus it should only be considered in selected cases (significant progression of the tumor mass) (Recommendation B).

11. What new drugs are available for the management of individuals with metastatic MTC?

In recent years, cumulative knowledge about the molecular mechanisms and intracellular signaling pathways involved in the pathogenesis of neoplasms such as MTC has allowed the development of novel targeted therapies.

Uncontrolled tyrosine-kinase receptor activation is one of the main mechanisms involved in cancer development and progression (213213  Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 2002;20:4368-80.,214214  Braga-Basaria M, Ringel MD. Clinical review 158: beyond radioiodine: a review of potential new therapeutic approaches for thyroid cancer. J Clin Endocrinol Metab. 2003;88:1947-60.) (D). Vascular endothelial growth factor (VEGF) performs critical functions in physiological and pathological angiogenesis, as well as in lymphangiogenesis (215215  Capp C, Wajner SM, Siqueira DR, Brasil BA, Meurer L, Maia AL. Increased expression of vascular endothelial growth factor and its receptors, VEGFR-1 and VEGFR-2, in medullary thyroid carcinoma. Thyroid. 2010;20:863-71) (D). Inhibition of VEGF action by blocking its receptors represents a novel approach to anticancer therapy (213213  Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 2002;20:4368-80.,216216  McMahon G. VEGF receptor signaling in tumor angiogenesis. Oncologist. 2000;5:3-10.,217217  Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist. 2004;9:2-10.) (B/D/D). Recent studies conducted with novel drugs that inhibit VEGF and its receptors in thyroid tumors yielded satisfactory results (218218  Ryan AJ, Wedge SR. ZD6474--a novel inhibitor of VEGFR and EGFR tyrosine kinase activity. Br J Cancer. 2005;92:S6-13.). In addition to VEGF, MTC pathogenesis also involves the presence of somatic or germline mutations in the RET proto-oncogene. RET comprises 21 exons and encodes a tyrosine-kinase receptor that is expressed in neural crest-derived cells (2 Punales MK, Rocha AP, Gross JL, Maia AL. Medullary thyroid carcinoma: clinical and oncological features and treatment. Arq Bras Endocrinol Metabol. 2004;48:137-46.,4 Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, et al. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet. 1994;3:237-41.) (D). Therefore, the use of drugs with anti-tyrosine kinase activities represents a novel therapeutic option for MTC management.

The initial results of clinical studies that used novel drugs such as tyrosine-kinase inhibitors to treat MTC were published in 2008 (www.clinicaltrials.gov). Clinical trials that employ such agents use RECIST to assess the responses to treatment as follows: complete response (disappearance of all target lesions), partial response (at least a 30% reduction in the sum of the longest target lesion diameters), progressive disease (at least a 20% increase in the sum of the longest target lesion diameters), and stable disease (neither sufficient shrinkage to qualify as a partial response nor sufficient increase to qualify as progressive disease) (219219  Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-16.) (D).

Overall, the partial response rate is approximately 30%, whereas stable disease is the most commonly achieved outcome. Two tyrosine-kinase inhibitors have been approved by the FDA (U. S. Food and Drug Administration) to treat rapidly progressive metastatic MTC, specifically vandetanib and cabozantinib (http://www.fda.gov/); however, only the former has been approved in Brazil.

Vandetanib is an oral agent that selectively targets the RET receptor, VEGF receptors (VEGFR), and the epidermal growth factor receptor (EGFR) (220220  Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, et al. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res. 2002;62:7284-90.,221221  Wedge SR, Ogilvie DJ, Dukes M, Kendrew J, Chester R, Jackson JA, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res. 2002;62:4645-55.) (D/D). A phase III clinical trial assessed the efficacy of vandetanib in 331 individuals with metastatic MTC who were randomized to receive vandetanib (300 mg) or a placebo. The results showed a significant increase in progression-free survival in the vandetanib-treated group, compared to the placebo group (30.2 vs. 19.2 months, respectively; hazard risk (HR) = 0.46, 95% confidence interval (CI) = 0.31-0.69). The rate of mortality at 2 – year follow-up was 15% (222222  Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134-41.,223223  Thornton K, Kim G, Maher VE, Chattopadhyay S, Tang S, Moon YJ, et al. Vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease: U.S. Food and Drug Administration drug approval summary. Clin Cancer Res. 2012;18(14):3722-30) (B). Another Phase II clinical study evaluated 19 patients using a reduced dose of vandetanib (100 mg/d). In this small group of patients, vandetanib used was associated with decreased progression-free survival with fewer adverse effects (224224  Robinson BG, Paz-Ares L, Krebs A, Vasselli J, Haddad R. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2010;95(6):2664-71.) (B). This same dose (100 mg/d) was also successfully used in children with MEN 2B (225225  Fox E, Widemann BC, Chuk MK, Marcus L, Aikin A, Whitcomb PO, et al. Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma. Clin Cancer Res. 2013;19(15):4239-48) (B). A recent systematic review on the use of vandetanib in MTC indicates the medication in patients with loco regional disease unresectable, symptomatic distant metastatic disease and disseminated metastatic disease (226226  Cooper MR, Yi SY, Alghamdi W, Shaheen DJ, Steinberg M. Vandetanib for the treatment of medullary thyroid carcinoma. Ann Pharmacother. 2014 Mar;48(3):387-94.) (B). Preclinical studies have indicated that RET codon 804 mutations (V804L, V804M) induce resistance to vandetanib (227227  Carlomagno F, Guida T, Anaganti S, Vecchio G, Fusco A, Ryan AJ, et al. Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene. 2004;23:6056-63.) (B).

Cabozantinib (XL184) is a powerful inhibitor of the hepatocyte growth factor receptor (MET), VEGFR2, and RET. A multicenter randomized study of 300 individuals with documented MTC progression during the previous 14 months found a significant increase in progression-free survival in the cabozantinib-treated group (140 mg/d), compared to the placebo group (11.2 vs. 4.0 months, respectively; RR = 0.28, 95% CI = 0.19-0.40, p < 0.0001) (228228  Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639-46.,229229  Hart CD, De Boer RH. Profile of cabozantinib and its potential in the treatment of advanced medullary thyroid cancer. Onco Targets Ther. 2013;6:1-7.) (B).

The effect of vandetanib or cabozantinib on the survival rate of MTC patients remains unknown, but interim analyses of the overall survival did not show a difference between the study drug-treated and placebo groups (222222  Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134-41.,228228  Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639-46.) (B/B).

Table 5 summarizes the main available drugs, as well as their corresponding targets and outcomes (222222  Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134-41.,228228  Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639-46.

229  Hart CD, De Boer RH. Profile of cabozantinib and its potential in the treatment of advanced medullary thyroid cancer. Onco Targets Ther. 2013;6:1-7.

230  Polverino A, Coxon A, Starnes C, Diaz Z, DeMelfi T, Wang L, et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res. 2006;66:8715-21.

231  Schlumberger MJ, Elisei R, Bastholt L, Wirth LJ, Martins RG, Locati LD, et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol. 2009;27:3794-801.

232  Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099-109.

233  Lam ET, Ringel MD, Kloos RT, Prior TW, Knopp MV, Liang J, et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol. 2010;28:2323-30.

234  Broutin S, Ameur N, Lacroix L, Robert T, Petit B, Oumata N, et al. Identification of soluble candidate biomarkers of therapeutic response to sunitinib in medullary thyroid carcinoma in preclinical models. Clin Cancer Res. 2011;17:2044-54.

235  Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25:884-96.

236  Carr LL, Mankoff DA, Goulart BH, Eaton KD, Capell PT, Kell EM, et al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res. 2010;16:5260-8.

237  Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004;165:35-52.

238  Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, et al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol. 2008;26:4708-13.

239  de Groot JW, Plaza Menacho I, Schepers H, Drenth-Diephuis LJ, Osinga J, Plukker JT, et al. Cellular effects of imatinib on medullary thyroid cancer cells harboring multiple endocrine neoplasia Type 2A and 2B associated RET mutations. Surgery. 2006;139:806-14.

240  Frank-Raue K, Fabel M, Delorme S, Haberkorn U, Raue F. Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma. Eur J Endocrinol. 2007;157:215-20.

241  de Groot JW, Zonnenberg BA, van Ufford-Mannesse PQ, de Vries MM, Links TP, Lips CJ, et al. A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab. 2007;92:3466-9.
-242242  Barroso-Sousa R, Lerario AM, Bezerra JE, Lourenço DM, Papadia C, Lin CS, et al. Complete resolution of hypercortisolism with sorafenib in a patient with advanced medullary thyroid carcinoma and ectopic ACTH syndrome. Thyroid. 2014;24(6):1062-6.) (B/B/B/C/B/C/B/C/C/B/C/B/C/C/B/C).

Table 5
Tyrosine kinase inhibitors for treatment of medullary thyroid carcinoma

The most common side effects of the tyrosine-kinase inhibitors include diarrhea, nausea, skin rash, hypertension, and fatigue (243243  Ferreira CV, Siqueira DR, Ceolin L, Maia AL. Advanced medullary thyroid cancer: pathophysiology and management. Cancer Manag Res. 2013;5:57-66.) (D). Additionally adverse events include neutropenia, leukopenia, hand-foot syndrome, stomatitis, proteinuria, abdominal pain, face swelling, thrombocytopenia and QTc prolongation – it is suggested that patients be monitored by conducting periodic electrocardiograms. The levothyroxine dose for replacement therapy usually needs to be increased. As a rule, the side effects of these inhibitors are well tolerated, and toxicity is controllable in most individuals. Nevertheless, severe adverse events have also been reported, including aspiration pneumonia, respiratory failure, septicemia, acute heart failure, and arrhythmia (222222  Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134-41.,231231  Schlumberger MJ, Elisei R, Bastholt L, Wirth LJ, Martins RG, Locati LD, et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol. 2009;27:3794-801.,236236  Carr LL, Mankoff DA, Goulart BH, Eaton KD, Capell PT, Kell EM, et al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res. 2010;16:5260-8.,244244  Wells SA Jr, Gosnell JE, Gagel RF, Moley J, Pfister D, Sosa JA, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol. 2010;28:767-72.

245  Scheffel RS, Dora JM, Siqueira DR, Burttet LM, Cerski MR, Maia AL. Toxic cardiomyopathy leading to fatal acute cardiac failure related to vandetanib: a case report with histopathological analysis. Eur J Endocrinol. 2013;168:K51-4.

246  Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011;29:2660-6.

247  Ahmed M, Barbachano Y, Riddell A, Hickey J, Newbold KL, Viros A, et al. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. Eur J Endocrinol. 2011;165:315-22.
-248248  Lenihan DJ, Cardinale DM. Late cardiac effects of cancer treatment. J Clin Oncol. 2012;30:3657-64.) (B/B/B/B/C/C/B/C).

Other therapeutic approaches for metastatic MTC are currently being investigated, including anti-CEA antibody-targeted radiotherapy, gene therapy, and other radiopharmaceuticals. Currently, such medications are only used in research protocols (249249  Bodei L, Handkiewicz-Junak D, Grana C, Mazzetta C, Rocca P, Bartolomei M, et al. Receptor radionuclide therapy with 90Y-DOTATOC in patients with medullary thyroid carcinomas. Cancer Biother Radiopharm. 2004;19:65-71.,250250  Chatal JF, Campion L, Kraeber-Bodere F, Bardet S, Vuillez JP, Charbonnel B, et al. Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group. J Clin Oncol. 2006;24:1705-11.) (D/D).

Recommendation 11

The results reported to date indicate that tyrosine-kinase inhibitors represent a relevant therapeutic option for the treatment of locally advanced or metastatic MTC (Recommendation A). Nevertheless, the corresponding data regarding long-term survival are not yet available. As a function of their side effect profiles, caution is required when identifying patients who might benefit from these drugs (Recommendation D). Currently, two tyrosine-kinase inhibitors, vandetanib and cabozantinib, have been approved by the FDA for the treatment of rapidly progressive metastatic MTC, while only the former has been approved in Brazil.

12. What should comprise the management of distant metastases?

Bone metastases

The incidence of bone metastases in thyroid carcinoma is approximately 5.0%, with median survival time after metastasis of 5.3 ± 1.3 years; patients with hypercalcemia have lower survival (251251  Wu K, Hou SM, Huang TS, Yang RS. Thyroid carcinoma with bone metastases: a prognostic factor study. Clin Med Oncol. 2008;2:129-34.) (B). The term skeletal-related event (SRE) is used to quantify the morbidity associated with bone metastases. The clinical determinants that compose the SRE include spinal cord compression, pathologic fractures, and the need for external radiotherapy or surgery to afford pain relief or control tumor-related hypercalcemia. Imaging exams are essential to determine the location and extent of the bone lesions; skeletal CT or MRI and FDG-PET/CT are the best currently available methods (1010  Giraudet AL, Vanel D, Leboulleux S, Auperin A, Dromain C, Chami L, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 2007;92:4185-90.,252252  Farooki A, Leung V, Tala H, Tuttle RM. Skeletal-related events due to bone metastases from differentiated thyroid cancer. J Clin Endocrinol Metab. 2012;97:2433-9.) (B/D)

The management of bone metastases depends on their number, localization and associated symptoms. If the disease is localized, surgical resection significantly improves patient prognosis and survival, and may be curative (253253  Lipton A, Theriault RL, Hortobagyi GN, Simeone J, Knight RD, Mellars K, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000;88:1082-90.) (D). Spinal cord compression indicates emergency surgery and the use of systemic corticosteroids. Active or imminent fractures in body-supporting bones require surgical treatment. Radiotherapy is useful for painful bone metastases, when surgery is contraindicated, or if resection was incomplete (252252  Farooki A, Leung V, Tala H, Tuttle RM. Skeletal-related events due to bone metastases from differentiated thyroid cancer. J Clin Endocrinol Metab. 2012;97:2433-9.,253253  Lipton A, Theriault RL, Hortobagyi GN, Simeone J, Knight RD, Mellars K, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000;88:1082-90.) (B/D).

The indication of bisphosphonates given per the intravenous route for the control of bone metastasis-related pain has been well established in other solid and hematological malignancies (254254  Vitale G, Fonderico F, Martignetti A, Caraglia M, Ciccarelli A, Nuzzo V, et al. Pamidronate improves the quality of life and induces clinical remission of bone metastases in patients with thyroid cancer. Br J Cancer. 2001;84:1586-90.

255  Ding X, Fan Y, Ma F, Li Q, Wang J, Zhang P, et al. Prolonged administration of bisphosphonates is well-tolerated and effective for skeletal-related events in Chinese breast cancer patients with bone metastasis. Breast. 2012;21:544-9.
-256256  Beuselinck B, Wolter P, Karadimou A, Elaidi R, Dumez H, Rogiers A, et al. Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases. Br J Cancer. 2012;107:1665-71.) (B). One recent study showed that zoledronic acid could effectively reduce skeletal-related events, including bone fractures, spinal cord compression, and hypercalcemia in individuals with differentiated thyroid carcinoma and bone metastases (257257  Orita Y, Sugitani I, Toda K, Manabe J, Fujimoto Y. Zoledronic acid in the treatment of bone metastases from differentiated thyroid carcinoma. Thyroid. 2011;21:31-5.) (B).

Liver metastases

The liver is the most frequent site of MTC metastases. The overall survival of patients with liver metastases who underwent radiofrequency ablation was 6 years (258258  Akyildiz HY, Mitchell J, Milas M, Siperstein A, Berber E. Laparoscopic radiofrequency thermal ablation of neuroendocrine hepatic metastases: long-term follow-up. Surgery. 2010;148(6):1288-93.) (B). The lesions are usually multiple and disseminated (259259  Mazzaglia PJ, Berber E, Milas M, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery. 2007;142(1):10-9.) (B). Treatment should be considered for large or progressive lesions, as well as for those associated with the occurrence of diarrhea and/or pain. The available options for treatment include chemoembolization (40-60% achieve partial response/disease stabilization) and tyrosine kinase inhibitor therapy for progressive disease (197197  Fromigue J, De Baere T, Baudin E, Dromain C, Leboulleux S, Schlumberger M. Chemoembolization for liver metastases from medullary thyroid carcinoma. J Clin Endocrinol Metab. 2006;91:2496-9.,243243  Ferreira CV, Siqueira DR, Ceolin L, Maia AL. Advanced medullary thyroid cancer: pathophysiology and management. Cancer Manag Res. 2013;5:57-66.) (C/D).

Lung and mediastinal metastases

Mediastinal lymph node involvement is frequent in advanced MTC, and its presence usually indicates an incurable disease. Therefore, when the lymph node affection is stable and not associated with clinical manifestations, expectant management is indicated, and the patients should be monitored with imaging methods and measurements of the calcitonin/CEA levels (188188  Pellegriti G, Leboulleux S, Baudin E, Bellon N, Scollo C, Travagli JP, et al. Long-term outcome of medullary thyroid carcinoma in patients with normal postoperative medical imaging. Br J Cancer. 2003;88:1537-42.) (B).

When airway compression or bleeding occur, surgery, radiotherapy, or radiofrequency ablation should be considered for the management of lung and/or mediastinal metastases (260260  Bezjak A. Palliative therapy for lung cancer. Semin Surg Oncol. 2003;21:138-47.) (D).

Brain metastases

Individuals with isolated brain metastases are candidates for surgical resection. Radiotherapy might be considered if surgery is not possible (261261  Börcek P, Asa SL, Gentili F, Ezzat S, Kiehl TR. Brain metastasis from medullary thyroid carcinoma. BMJ Case Rep. 2010 Dec 29;2010.

262  McWilliams RR, Giannini C, Hay ID, Atkinson JL, Stafford SL, Buckner JC. Management of brain metastases from thyroid carcinoma: a study of 16 pathologically confirmed cases over 25 years. Cancer. 2003;98:356-62.
-263263  Chiu AC, Delpassand ES, Sherman SI. Prognosis and treatment of brain metastases in thyroid carcinoma. J Clin Endocrinol Metab. 1997;82:3637-42.) (B).

Recommendation 12

The currently available treatments for individuals with distant metastases of MTC, which include surgery, chemotherapy, radiotherapy, and tyrosine-kinase inhibitors, are palliative and might be indicated in selected cases to control the disease progression or to improve the patient’s quality of life.

13. When are radioactive iodine treatment and/or levothyroxine suppressive therapy indicated in individuals with MTC?

Unlike differentiated thyroid cancer, which originates in the follicular cells, MTC originates in the C or parafollicular cells; therefore, radioactive iodine treatment and/or levothyroxine suppressive therapy are not indicated for MTC management (7373  Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612.) (D). In recent studies, the use of radioactive iodine did not show any effects relevant to the postoperative management of individuals with MTC (264264  Finny P, Jacob JJ, Thomas N, Philip J, Rajarathnam S, Oommen R, et al. Medullary thyroid carcinoma: a 20-year experience from a centre in South India. ANZ J Surg. 2007;77:130-4.) (B).

Recommendation 13

Neither radioactive iodine treatment (Recommendation B) nor levothyroxine suppressive therapy is indicated in MTC (Recommendation B).

SUMMARY OF RECOMMENDATIONS

To summarize, the main recommendations for the diagnostic assessment, treatment, and follow-up of MTC are as follows:

PART I: MTC – DIAGNOSIS

  1. A thyroid nodule is the most common clinical manifestation of MTC. MTC should be specifically suspected in individuals with family history of MTC, RET mutations or associations with pheochromocytoma, hyperparathyroidism, cutaneous lichen amyloidosis, Marfanoid habitus, or mucosal neuromas.

  2. FNAB should be included in assessments of thyroid nodules suspected of MTC. The differential diagnosis might be facilitated by the use of additional techniques such as the measurement of calcitonin in the FNAB washout fluid and immunocytochemistry.

  3. MTC screening via a serum calcitonin measurement in individuals with thyroid nodules remains controversial. Because of problems with reference value standardization and its doubtful cost-effectiveness, the measurement of serum calcitonin is not indicated in the routine investigation of thyroid nodules.

  4. The preoperative calcitonin levels correlate with the tumor size and the presence of local or distant metastases. The individuals with suspected MTC and calcitonin levels > 150 ng/mL must be investigated for the presence of locoregional and distant metastases by imaging tests (Flowchart 1).

  5. Neck US is indicated in all individuals with suspected MTC (Recommendation B). In addition to identifying characteristics suggestive of malignancy in the thyroid nodules and allowing the performance of US-guided FNAB, US is the most sensitive test for detecting neck metastases and thus contributes to therapeutic planning.

  6. In individuals with neck metastases and/or calcitonin levels > 400 mg/mL, the presence of distant metastases should be investigated before surgery. The presence of pheochromocytoma must be investigated by the measurement of plasma fractionated metanephrines or urine metanephrine levels, if not available the blood measurement. The presence of hyperparathyroidism might be investigated through a serum calcium level measurement after adjusting for the albumin concentration.

  7. A molecular assessment is indicated for all individuals with C cell hyperplasia, (familial or apparently sporadic) MTC, and/or MEN 2. The molecular diagnosis might guide the choice of therapeutic procedures might guide the choice of therapeutic procedures and could consequently change the natural course of disease, indicate genetic counseling, and help to establish the disease prognosis.

  8. All first-degree relatives of individuals with MTC and germline RET mutations should be subjected to molecular screening.

  9. The knowledge of the type of RET mutation provides relevant information about the clinical presentation of MEN 2 and the biological behaviors of the associated neoplasms

  10. The presence of CLA or Hirschsprung’s disease indicates the suspected occurrence of hereditary MTC and therefore the need to perform a RET molecular assessment.

  11. In asymptomatic cases or in the absence of adrenal masses, urine and/or fractionated plasma metanephrines measurements should begin at 8 years of age in individuals with MEN 2B or 2A who carry mutations in codons 630 or 634, and after 20 years of age in the remainder of individuals with MEN 2A. Hyperparathyroidism screening must be performed annually by measuring the total calcium and albumin levels, starting at 8 years age in carriers of mutations in RET codons 630 and 634 and at 20 years of age in the remainder of individuals with MEN 2A.

PART II. MTC – SURGICAL TREATMENT

  1. The surgical treatment recommended for individuals with MTC limited to the thyroid gland is total thyroidectomy and elective dissection of the central compartment.

  2. In cases with locoregional disease, total thyroidectomy with central compartment lymph node dissection is indicated (B). Lateral lymph node dissection is indicated when metastases are present or suspected (B). Less aggressive surgery is indicated in cases with advanced local disease and/or distant metastases to achieve local disease control while preserving the patient’s voice, deglutition, and parathyroid function.

  3. In cases with a postoperative MTC diagnosis, completion thyroidectomy and prophylactic central dissection are indicated. Watchful waiting might apply to selected individuals.

  4. In cases without preoperative hyperparathyroidism, the “in situ” preservation of the parathyroid glands is always desirable. When the glands are accidentally removed or there is a risk of devascularization, the glands should be autografted into the sternocleidomastoid muscle. In cases with hyperparathyroidism, MEN 2A, or prior surgery for MTC, the affected parathyroid gland should be identified with imaging methods to decide upon a subtotal or total parathyroidectomy, followed by a forearm autograft.

  5. The surgical approach in asymptomatic carriers RET proto-oncogene mutations should consider the risk stratification according to the affected codon, as follows:– Group D (MEN 2B): total thyroidectomy within the first year of life. In cases with evidence of lymph node metastases, nodule sizes > 5 mm, or serum calcitonin levels > 40 pg/mL, central compartment dissection is also indicated. Individuals older than 1 year of age are indicated for (elective) “prophylactic” central dissection.– Group C: total thyroidectomy before 5 years of age.– Groups A and B: total thyroidectomy after 5 years of age in the absence of evidence of MTC (normal serum calcitonin levels and neck US). Contrariwise, surgery should be performed before 5 years of age. Individuals in groups A, B, and C should be subjected to central compartment dissection when there is clinical and/or imaging evidence of metastatic disease, the nodule size is ≥ 5 mm, and the serum calcitonin level is > 40 pg/mL (D).

  6. Individuals with advanced local disease or distant metastases should be subjected to less aggressive surgeries aimed at achieving local disease control while preserving the patient’s voice, deglutition, and parathyroid functions, as well as avoiding hemorrhagic complications due to the invasion of vascular structures (D).

  7. Elective superior mediastinal dissection is usually performed during surgery for MTC. The dissection of the lower mediastinum should be considered only as a palliative treatment in patients with high risk of airway obstruction or bleeding.

  8. In individuals with pheochromocytoma and MTC, adrenalectomy should precede thyroidectomy. Therefore, the presence of pheochromocytoma should be established or ruled out before thyroid surgery is performed.

PART III. MTC – FOLLOW-UP

  1. Serum calcitonin and CEA levels should be measured 2-3 months after surgery. Once the calcitonin levels normalize, this measurement should be repeated after 6-12 months. Persistently elevated calcitonin/CEA levels are suggestive of disease persistence or recurrence and indicate the need for further investigation to establish the disease extension.

  2. The main prognostic factors of survival in individuals with MTC are age, the tumor stage at the time of diagnosis, and the calcitonin and CEA doubling times. In individuals with hereditary MTC, the main prognostic factor of cure and survival is the performance of a prophylactic thyroidectomy following the identification of RET gene mutations.

  3. Basal calcitonin levels < 150 pg/mL are associated with the presence of locoregional disease, and neck US should be the first test used in the assessment. The likelihood of detecting distant metastases is higher among patients with calcitonin levels > 150 pg/mL. In such cases, chest CT, abdominal MRI, and bone scintigraphy should be performed to establish the presence of mediastinal and lung, liver, and bone metastases, respectively.

  4. Measurements of serum calcitonin levels should be performed every 6-12 months for a still-undefined period of time in individuals with undetectable levels after surgery due to the risk of disease relapse. Measurements of the calcitonin level in the FNAB washout fluid might facilitate the diagnoses of suspected lesions.

  5. The pentagastrin/calcium stimulation test is not indicated for the follow-up of individuals with undetectable basal serum calcitonin, as positive results denote residual diseases that are difficult to locate with imaging methods.

  6. Serum calcitonin is the most relevant biomarker for the follow up individuals with MTC. Discrete increases in the calcitonin levels (< 150 pg/mL) usually denote the presence of locoregional disease. More substantial elevations (> 150 pg/mL) are suggestive of distant metastases. The best methods for investigating metastases are US for the neck, CT for the chest, MRI for the liver, and bone scintigraphy and/or axial skeleton MRI for the bones.

  7. Individuals with elevated serum calcitonin levels and negative imaging tests should be assessed at least every 6 months, and these assessments should include measurements of the calcitonin and CEA levels to calculate their DTs.

  8. Systemic treatment should be considered for symptomatic individuals and/or those with documented significant disease progression (according to radiological methods and/or a calcitonin or CEA DT < 6 months).

  9. Advanced MTC metastatic disease might be attended by systemic hormonal changes secondary to the increased calcitonin levels and/or the ectopic production of some specific hormones. Treatment should be planned on an individual basis according to the clinical manifestations of the existing dysfunction.

  10. Radiotherapy should be considered for local disease control, the palliative treatment of painful bone metastases or those at risk of fracture, and for the treatment of hemoptysis or airway obstruction in individuals with extensive mediastinal and/or lung involvement. The effects of conventional chemotherapy are limited, and thus it should only be considered in selected cases (significant progression of the tumor mass).

  11. The results reported to date indicate that tyrosine-kinase inhibitors represent a relevant therapeutic option for the treatment of locally advanced or metastatic MTC (Recommendation A). Nevertheless, the corresponding data regarding long-term survival are not yet available. As a function of their side effect profiles, caution is required when identifying patients who might benefit from these drugs (Recommendation D). Currently, two tyrosine-kinase inhibitors, vandetanib and cabozantinib, have been approved by the FDA for the treatment of rapidly progressive metastatic MTC, while only the former has been approved in Brazil. Advanced metastatic MTC might be associated with systemic hormonal changes consequent to increased calcitonin levels and/or the ectopic production of specific hormones. Treatment should be established on an individual basis according to the clinical manifestations of the existing dysfunction.

  12. The currently available treatments for individuals with distant metastases of MTC, which include surgery, chemotherapy, radiotherapy, and tyrosine-kinase inhibitors, are palliative and might be indicated in selected cases to control the disease progression or to improve the patient’s quality of life.

  13. Neither radioactive iodine treatment nor levothyroxine suppressive therapy is indicated in MTC.

Acknowledgments

Wwe would like to thank Dr. Carmen Cabanelas Pazos de Moura, President of the Thyroid Department of the Brazilian Society of Endocrinology & Metabolism, for her support of this work. We are also grateful to Dr. Nathalia Carvalho de Andrada [Projeto Diretrizes da Associação Médica Brasileira, Conselho Federal de Medicina (AMB/CFM)] for reviewing the strength of evidence and the degree of recommendations of this consensus.

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Publication Dates

  • Publication in this collection
    Oct 2014

History

  • Received
    22 Apr 2014
  • Accepted
    12 July 2014
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