甲状腺髓样癌的诊治

C o p y r i g h t © A B E &M t o d o s o s d i r e i t o s r e s e r v a d o s .consensusDiagnosis, treatment, and follow-up of medullary thyroid carcinoma: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and MetabolismDiagnóstico, tratamento e seguimento do carcinoma medular de tireoide: recomendações do Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e MetabologiaAna Luiza Maia 1, Debora R. Siqueira 1, Marco A. V . Kulcsar 2, Alfio J. Tincani 3, Glaucia M. F . S. Mazeto 4, Lea M. Z. Maciel 5ABSTRACTIntroduction: 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 Transfec-tion (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, treat-ment, 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 diag-nosis, 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: MTC should be suspected in individuals who present with thyroid nodules and family histories of MTC, associations with pheochromocytoma and hy-perparathyroidism, and/or typical phenotypic characteristics such as ganglioneuromatosis and Marfanoid habitus. Fine-needle nodule aspiration, serum calcitonin measurements, and ana-tomical-pathological examinations are useful for diagnostic confirmation. Surgery represents the only curative therapeutic strategy. The therapeutic options for metastatic disease remain limited and are restricted to disease control. Judicious postoperative assessments that focus on the identification of residual or recurrent disease are of paramount importance when defining the follow-up and later therapeutic management strategies. Arq Bras Endocrinol Metab. 2014;58(7):667-700KeywordsMedullary thyroid carcinoma; MEN 2A; MEN 2B; RET proto-oncogene; diagnosis; treatment; follow-upRESUMOIntrodução: O carcinoma medular de tireoide (CMT) origina-se das células parafoliculares da ti-reoide 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 RET1Thyroid Unit, Division ofEndocrinology, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil 2Clinical Surgery Head and Neck, Instituto do Câncer do Estado de São Paulo (Icesp), Universidade de São Paulo (USP), São Paulo, SP , Brazil 3Department of Head and Neck Surgery, Department of Surgery, Universidade Estadual de Campinas (Unicamp), Campinas, SP , Brazil 4Discipline of Endocrinology and Metabolism, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista Júlio de Mesquita Filho (Unesp), Botucatu, SP , Brazil 5Division of Endocrinology,Department of Internal Medicine, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP , BrazilCorrespondence to:Ana Luiza MaiaUnidade de Tireoide,Serviço de Endocrinologia,Hospital de Clínicas de Porto Alegre Rua Ramiro Barcelos, 235090035-003 – Porto Alegre, RS, Brazil almaia@ufrgs.brReceived on April/22/2014Accepted on July/12/2014DOI: 10.1590/0004-2730000003427C o p y r i g h t © A B E &M t o d o s o s d i r e i t o s r e s e r v a d o s .Diagnosis, treatment, and follow-up of medullary thyroid carcinoma(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 base-adas 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 defini-das 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 diag-nóstico 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 feocromoci-toma, hiperparatireoidismo e/ou fenótipo sindrômico característico, como ganglioneuromatose e habitus marfanoides. A punção aspirativa por agulha fina do nódulo, a dosagem de calcito-nina 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. Arq Bras Endocrinol Metab. 2014;58(7):667-700DescritoresCarcinoma medular de tireoide; NEM 2A; NEM 2B; proto-oncogene RET ; diagnóstico; tratamento; seguimentoINTRODUCTIONMedullary thyroid carcinoma (MTC) originates in the thyroid parafollicular or C cells and re-presents 3-4% of the malignant neoplasms that affect this gland (1) (A). Overall, 10,590 new cases of thyroid cancer were estimated among Brazilian women in 2012 (National Cancer Institute/Instituto Nacional do Cân-cer [Inca]; .br/estimativa/2012). As-suming 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). The most common form of this syndrome is MEN 2A, which is characterized by MTC (95%), pheochromo-cytoma (50%), and hyperparathyroidism (20%), while MEN 2B includes MTC (90%), pheochromocytoma (45%), ganglioneuromatosis (100%), Marfanoid habi-tus (65%), and eye abnormalities (e.g ., thickened cor-neal nerves, conjunctivitis sicca, and an inability to cry tears). F amilial MTC (F MTC) is defined by thep resence of MTC alone, and its diagnosis is based on the absence of pheochromocytoma or hyperparathy-roidism in 2 or more family generations or the pre-sence of mutations classically associated with F MTC (2,3) (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) (A). Approximately 50% of sporadic MTC cases exhibit somatic mutations in the RET gene (4,5) (A/B).Calcitonin is a specific biomarker with a high sen-sitivity 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 (6,7) (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 (ap-proximately the fifth or sixth decade). Neck lymph node metastases are detected in approximately 50% of cases at the time of diagnosis, while distant metas-tases occur in 20% of cases (8-11) (B). Early surgical intervention is the only curative therapeutic approach (11) (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% (12) (B).C o p y r i g h t © A B E &M t o d o s o s d i r e i t o s r e s e r v a d o s .The recommendations described below resulted from the efforts of the Thyroid Department of the Brazilian Society of Endocrinology and Metabolismto formulate evidence-based clinical guidelines for the care of individuals with MTC. Our main goal is to as-sist clinicians with the selection of the best strategies for patient management according to the characteristics of the Brazilian health system.MATERIALS AND METHODSThe present consensus complies with the strategic po-licy of the Thyroid Department of the Brazilian Soci-ety of Endocrinology and Metabolism for the develop-ment 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 (Con-selho Federal de Medicina [CFM]), served as a model for the present recommendations. The authors were selected according to their academic and scientific ac-tivities 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 re-commendation or strength of evidence (Table 1) of the studies was established according to the Oxford clas-sification (13) (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.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 recommenda-tions presented herein summarize the relevant aspects of each clinical question and are categorized as a func-tion of the evidential strength on which they are based, as described in table 1.PART I: MTC: DIAgNOSIS1. When should we suspect MTC?The most common clinical presentation of MTC is the appearance of a single thyroid nodule. Thyroid nodu-les might also eventually appear within the context of a multinodular goiter or might represent an incidental finding in imaging exams of the neck (14) (D). Neck lymph node enlargement is present in 50% of these ca-ses (8,9) (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, hyperpara-thyroidism), cutaneous lichen amyloidosis on the in-terscapular region, ganglioneuromas, typical facies, or a history of thyroid cancer and/or of RET mutations in first-degree relatives might be suggestive of heredi-tary MTC (2-4,15) (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 (2,3,15) (D/D/C).There are no specific clinical findings that permit a firm diagnosis of MTC. F or this reason, if CMT is suspected, the physician should order diagnostic tests, including fine-needle aspiration biopsy (FNAB) and se-rum calcitonin measurements.Recommendation 1A thyroid nodule is the most common clinical manifes-tation of MTC. MTC must be specifically suspected in individuals with family history of thyroid cancer, RET mutations, and/or associations with pheochromocyto-ma, hyperparathyroidism, cutaneous lichen amyloidosis and/or typical findings upon physical examination suchDiagnosis, treatment, and follow-up of medullary thyroid carcinomaTable 1. Definition of the grades of recommendation and strength of evidenceA Experimental or observational studies with greaterconsistencyC o p y r i g h t © A B E &M t o d o s o s d i r e i t o s r e s e r v a d o s .as Marfanoid habitus and mucosal neuromas (Recom-mendation 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 diag-nostic assessment of thyroid nodules. The characteristic cytological findings in MTC include the presence of predominantly isolated cells or cells arranged in isola-ted cohesive groups, with a round-to-oval, polyhedral, or fusiform shape, and the predominance of 3-dimen-sional 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 detec-ted by Congo red staining. Further cytological findings include the presence of fusiform cells and cytoplasmic (comet-like) projections (16) (B).The sensitivity of FNAB for diagnosing MTC in a thyroid nodule varies from 46.1-63% (17-19) (B). Al-though non-diagnostic, the FNAB findings in MTC are indicative of surgery in 99% of cases (17-19) (B). Ap-proximately 82% of MTC cases are correctly identified by FNAB, while 9% are false-negative results (18,19) (B).The most frequent reasons for FNAB failure are in-adequate sampling and multinodular goiters (because the malignant nodule might not be selected for assess-ment) (20) (B). Additionally, differential diagnosis be-tween MTC and other malignant thyroid neoplasms (particularly follicular lesions, Bethesda category III or IV) might be difficult because the cytological findings can be similar (20,21) (B).The measurement of calcitonin in the washout fluid has been recommended to improve the diagnostic sensitivity of FNAB for MTC (22,23) (B/C). In a re-cent 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 (24) (B).The failure to diagnose MTC in a cytological ex-amination might negatively impact the therapeutic management of patients (20) (B). Immunochemical staining for calcitonin might be useful in doubtful cas-es (25) (C). Other methods that might facilitate the diagnosis of MTC include scanning electron micros-copy and assessments of calcitonin mRNA expression; however, these are not part of the diagnostic routine (25-28) (C).Recommendation 2FNAB should be included in assessments of thyroid no-dules suspected of MTC (Recommendation B). Diag-nosis might be facilitated by the use of additional te-chniques such as calcitonin measurement in the FNAB washout fluid (Recommendation B) and immunocyto-chemistry (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 positi-ve 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 (29) (A). Ac-cording 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 (30) (D). In comparison with the ultrasensi-tive calcitonin, the pentagastrin test still shows better diagnostic capability (31) (A). However, the penta-gastrin stimulation test is not available in Brazil. The calcium stimulation test can be used as an alternati-ve (32) (B). Nevertheless, recent studies have shown that with the improved sensitivity of the new assays, both basal and stimulated calcitonin have similar ac-curacy, which reduces the relevance of the stimulation tests in multiple conditions (33) (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, hyper-parathyroidism, neuroendocrine neoplasms, lung and prostate tumors and autoimmune thyroiditis (34,35) (D/B), which are considered classic causes of false-positive results. Presence of heterophile antibodies (human antibodies with broad reactivity with anti-bodies of other species) can also interfere in dosage, causing falsely elevated values (or, less frequently, false-positive results) (36) (B). Of note, recent study conducted in Brazil found no changes in the serumDiagnosis, treatment, and follow-up of medullary thyroid carcinomaC o p y r i g h t © A B E &M t o d o s o s d i r e i t o s r e s e r v a d o s .calcitonin levels of individuals with Hashimoto’s thy-roiditis (37) (B). False-negative results might be due to the hook effect and, less often, to non-calcitonin-secreting MTC (38,39) (C).Compared with FNAB, the sensitivity of the calcito-nin measurement for preoperative diagnosis of MTC is higher (approximately 100% sensitivity and 95% speci-ficity) (18,40,41) (B). Individuals with MTC that was diagnosed from a calcitonin measurement during the investigation of thyroid nodules exhibit better postop-erative outcomes than do those diagnosed by FNAB, with 10-year survival rates of 86.8% and 43.7%, respec-tively (42) (B).In North America, studies of cost-effectiveness ob-tained results favorable to the inclusion of calcitonin measurements in initial thyroid nodule assessments (43,44) (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 calcito-nin measurements (42,45-47) (B). Additionally, the reproducibility of those results in our milieu is doubt-ful. For those reasons, the Brazilian consensus for thy-roid nodules does not recommend the measurement of serum calcitonin in the initial nodule assessment (14) (B). However, measurement of calcitonin in the FNAB washout fluid may be useful in nodules with undeter-mined results (Bethesda category III/IV), considering the difficulties of F NAB to differentiate MTC from other thyroid malignancies (particularly follicular le-sions) (24) (B).The prevalence of MTC in individuals with multi-nodular goiters varies from 0-3.1% (48) (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 (49) (D). Additionally, small MTC foci might not be identified with thyroid ultrasound (US). For all those reasons, the serum calci-tonin measurement might be useful for detecting MTC in cases of multinodular goiter (50,51) (A).Recommendation 3MTC screening via a serum calcitonin measurement in individuals with thyroid nodules remains contro-versial. Because of problems with reference value stan-dardization and its doubtful cost-effectiveness, the measurement of serum calcitonin is not indicated inthe routine investigation of thyroid nodules (Recom-mendation 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 calcito-nin, CEA, amyloid, somatostatin, ACTH, vasoactive intestinal peptide (VIP), and serotonin, among others (52,53) (B). Calcitonin is the most important bioma-rker and is used in the diagnosis, surgical planning, pos-toperative management, and prognosis of individuals with MTC (54) (D).In individuals with MTC, the preoperative calcito-nin levels correlate with the tumor size and the presen c e of metastases (6,7) (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 lev-els of 10-40 pg/mL, while metastatic disease should be suspected at levels of 150-400 pg/mL. The presen-ce of lymph node metastases or calcitonin levels > 400 pg/mL indicate the need to identify distant metastases (6,7) (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 metas-tases in the ipsilateral central and lateral neck compart-ments, while levels > 100 ng/mL correlate with contra-lateral lymph node metastases and distant metastases. Values > 30 ng/mL were found to correlate with low cure rates (55) (B).The preoperative serum calcitonin levels seem to cor-relate more strongly with extensions of MTC, as com-pared 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 (56) (B).Recommendation 4Preoperative calcitonin levels correlate with the tumor size and stage and indicate the presence of local and/or distant metastases (Recommendation B). The indivi d uals 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 Recom-mendation 6, Flowchart 1) (Recommendation B).Diagnosis, treatment, and follow-up of medullary thyroid carcinomaC o p y r i g h t © A B E &M t o d o s o s d i r e i t o s r e s e r v a d o s .5. What is the value of neck US for the diagnosis of MTC?Thyroid US is a relevant part of a thyroid nodule assess-ment. 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, in-cluding hypoechogenicity, microcalcifications, irregular margins, predominantly central vascularization, and the presence of enlarged neck lymph nodes (57-59) (B).Most individuals with MTC (> 90%) exhibit hy-poechoic nodules, intranodular calcifications, and an absence of the halo sign on US; further possible findings include the presence of intranodular (79%) and peri-nodular (50%) blood flow (60) (B). Some cases exhibit intranodular bright echogenic foci that correspond to amyloid-surrounded calcium deposits (61) (B).Neck US is the most sensitive imaging method for neck metastasis detection (10) (B). Approximately 75% of patients with MTC that is clinically detectable by palpation exhibit lymph node metastases (8) (B). As the presence of lymph node and/or distant metastases indi-cates the need for changes in the therapeutic manage-ment, US might be considered indispensable for treat-ment 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 (62) (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) (63) (B). One impor-tant limitation of US is that it is operator-dependent, and therefore the results vary as a function of the opera-tor’s experience. This most likely explains why a larger number of neck lymph node metastases are detected with surgical dissection, compared to US. Neverthe-less, 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) (64) (B). Preoperative neck US is a valuable tool in assess-ing 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 (63) (B).Recommendation 5Neck 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 plan-ning (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 in-terferes with surgery planning in individuals with MTC. Neck metastases appear early during the course of MTC (9,65) (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) (10,11,66,67) (B/B/B/A).Neck US must be performed in all affected indivi-duals (56-58) (B). Findings suggestive of neck metasta-ses or calcitonin levels > 400 pg/mL indicate the needDiagnosis, treatment, and follow-up of medullary thyroid carcinomaThyroid nodule Suspicious FNAB*? Serum calcitonin measurementMTCRET molecular analysisExcluded MTC Evaluation/management for FNAB suspicious for malignancyExcluded pheochromocytomaPheochromocytoma Adrenal surgeryCEA, calcium and 24-urinary metanephrinesCalcitonin levels > 400 pg/mL Evaluation of distant metastasisNeck USTotal thyroidectomy with or without neck dissection* Findings suggestive of MTC: triangular or polygonal cells, cytoplasmic granules,eccentric nuclei with coarsely granular chromatin and amyloid.Flowchart 1. Initial diagnostic approach of medullary thyroid carcinoma.。

甲状腺髓样癌应该做哪些检查？
*导读：本文向您详细介甲状腺髓样癌应该做哪些检查，常用的甲状腺髓样癌检查项目有哪些。

以及甲状腺髓样癌如何诊断鉴别，甲状腺髓样癌易混淆疾病等方面内容。

*甲状腺髓样癌常见检查：
常见检查：神经元特异性烯醇化酶（NSE）、降钙素、CT检查、颈部MRI检查、正电子发射计算机断层扫描(PET)
*以上是对于甲状腺髓样癌应该做哪些检查方面内容的相关叙述，下面再来看看甲状腺髓样癌应该如何鉴别诊断，甲状腺髓样癌易混淆疾病。

*甲状腺髓样癌如何鉴别？：
*温馨提示：以上内容就是为您介绍的甲状腺髓样癌应该做哪些检查，甲状腺髓样癌如何鉴别等方面内容，更多更详细资料请关注疾病库，或者在站内搜索“甲状腺髓样癌”了解更多，希望以上内容可以帮助到大家！。

甲状腺髓样癌甲状腺髓样癌实际上并非甲状腺癌，它来源于分泌降钙素的甲状腺滤泡旁细胞(又称C细胞)，是神经内分泌细胞，和甲状腺滤泡细胞无关。

1959年由Hazand等首先提出作为一个独立临床病理类型，它只占甲状腺肿瘤一小部分（约占3-12%），其发病、诊断和治疗都独具特点。

疾病分类/甲状腺髓样癌编辑根据是否具有遗传性，MTC可分为散发性和遗传性两大类：1.散发性MTC：临床上最多见，约占MTC的75- 80%，多为中老年，女性稍多；2.遗传性MTC：临床上较少见，约占MTC的20- 25%，发病年龄较散发性MTC提前10-20年左右，男女发病率无差异，一个家族中可以同时或先后有多人患病。

又细分为以下3种类型：▶多发性内分泌腺瘤2A(MEN2A)：占所有遗传性MTC80%,此型会同时发生MTC、嗜铬细胞瘤和甲状旁腺增生▶多发性内分泌腺瘤2B(MEN2B)：无甲状旁腺疾病，以粘膜多发性神经瘤伴MTC和（或）肾上腺嗜铬细胞瘤为特点，是遗传性MTC 中恶性程度最高的类型；▶家族非多发性内分泌腺瘤性MTC（FMTC)：此型被认为是MEN2A的一种变异类型，MTC是其唯一的特征，是遗传性MTC中恶性程度最低的类型。

疾病原因/甲状腺髓样癌编辑发病原因1. MTC发病主要原因是RET原癌基因突变；2. 约95%遗传性MTC和70%散发性MTC是由位于10q11.2原癌基因RET突变所致。

发病机制1. 主要发病机制为RET原癌基因突变后，导致甲状腺C细胞内外区蛋白构象的改变，进而诱导细胞增生过度而发生癌变；2. RET原癌基因定位于10号染色体长臂，含21个外显子，编码一种属于酪氨酸激酶受体超家族的跨膜蛋白；3. 目前发现与MTC有关的RET基因突变位点共有约20余个，这些突变可以分别导致胞外区和胞内区蛋白构象的改变，此类构象的改变可增强RET的转化能力，激发酪氨酸激酶自动磷酸化，诱导细胞增生过度以致癌变。

病理生理/甲状腺髓样癌编辑1. MTC起源于甲状腺C细胞（属于神经内分泌细胞），有很强生物学活性，合成多种生物学物质，包括降钙素（CT）、促肾上腺皮质激素（ACTH）、组织胺、癌胚抗原和血管活性肽；2. “C细胞增生”（CCH）表现为甲状腺实质中的多灶性C细胞簇；3. CCH是MTC先期过程，患者可先发生CCH，后发展为早期具有侵袭性的甲状腺微小髓样癌，最后成为肉眼可见的MTC。

《甲状腺髓样癌诊断与治疗中国专家共识（2020版）》要点甲状腺癌病人中，90%以上为分化型甲状腺癌（DTC），而甲状腺髓样癌（MTC）的发病率较低，且有其独特的临床病理特征，故而误诊、漏诊和不规范治疗现象仍然普遍存在。

MTC是起源于甲状腺滤泡旁细胞（C细胞）的恶性肿瘤。

C细胞属于 APUD 系统，具有合成分泌降钙素（Ctn）及降钙素基因相关肽的作用，因此，MTC亦被认为是神经内分泌肿瘤之一。

1 MTC的分类及流行病学根据疾病的遗传特性，将MTC分为遗传性和散发性两大类。

2 RET基因筛查、遗传咨询及干预时机2.1 RET基因筛查和遗传咨询[推荐1]：对于以下人群可推荐进行RET基因筛查和遗传咨询：（1）散发性MTC病人本人。

（2）遗传性MTC病人本人及一级亲属。

（3）在儿童或婴儿期出现MEN2B表现病人的父母。

（4）皮肤苔藓淀粉样变的病人。

（5）先天性巨结肠病病人，携带RET基因10号外显子突变。

（证据等级：D；推荐等级：B）[推荐2]：进行RET基因筛查的具体目标位点包括：（1）MEN2A的基因筛查。

需要检查的RET基因突变位点主要包括10号外显子的第 609、611、618、620 密码子、11号外显子的第630、634密码子。

若上述检查未发现明确的突变位点，或临床表型与检查结果不一致时，应进一步采用RET基因编码区全测序进行筛查。

（2）MEN2B 的基因筛查：需要检查的RET基因突变位点主要包括16号外显子的M918T突变和15号外显子的A883F突变，若结果为阴性则行需要RET基因编码区全测序。

（证据等级D；推荐等级：A）[推荐3]：除计划使用选择性RET抑制剂治疗晚期MTC外，不常规筛查MTC病人的体系RET突变。

（证据等级：D；推荐等级：B）[推荐4]：在十分罕见的家系中，会出现受检者符合MEN2A或MEN2B 临床诊断标准，但整个RET编码区均没有基因突变的情况。

这种情况下有风险的亲属应当采用传统的筛查MTC、嗜铬细胞瘤以及 HPTH 的方法来进行阶段性检查。

甲状腺髓样癌外科手术切除首选，不管是散发性还是家族性甲状腺髓样癌，手术应采取根治术，应该进行甲状腺全切除，将切下的甲状旁腺移植在前臂。

对颈部淋巴结是否需要进行预防性切除，有些医生主张对病人进行颈部淋巴结的预防性切除，包括舌骨至颈静脉之间的淋巴结。

有些医生不主张颈部淋巴结清扫术，除非发现有肿瘤侵犯内颈静脉和（或）颈锁乳突肌，没有资料证明颈部淋巴结广泛清扫对病人预后有影响。

降钙素血浆半寿期为3-30h，手术后30-40d，测定血清降钙素，这足以使手术前升高的降钙素下降。

如果基础和五肽胃泌素剌激后降钙素测不到，可以肯定病人得到治愈。

遗憾的是即使很细心地清扫颈部淋巴结手术，也只有不足40%-50%病人得到治愈。

对降钙素升高的病人，需要进一步定位，肝脏和颈部的B超，纵隔和肺部CT，全身骨扫描可以发现骨转移。

MIBG可以探测大的转移灶，对微小转移灶往往不够敏感。

对高度怀疑的病人，静脉插管分段取血测定降钙素帮助定位，也在试验阶段。

分类甲状腺髓样癌是甲状腺滤泡旁细胞癌，只占甲状腺癌的8%-10%，有散发性和家族性2类，任何年龄都可以发病，多发性内分泌腺病（MEN）病人的甲状腺髓样癌发病峰值年龄在20-30岁。

散发性病人的发病峰值年龄在40-60岁，女性略多于男性，女性：男性为1.2：1。

由于积极的外科切除，甲状腺全切和颈部中线淋巴结清扫，使5年和10年存活率从过去的48%和12%分别提高到88%和78%。

甲状腺髓样癌中80%是散发性，20%是遗传性的，家族性病人为常染色体显性遗传，有不同的表现率。

遗传性甲状腺髓样癌分为：MEN-Ⅱa，表现为甲状腺髓样癌、嗜铬细胞瘤和甲旁亢；MEN-Ⅱb也称为MEN-Ⅲ型，表现为甲状腺髓样癌、嗜铬细胞瘤、黏膜神经瘤、肠道神经节瘤和马方体态（Marfanoid habitus）和骨路畸形；非内分泌家族性甲状腺髓样癌，不伴有其他内分泌瘤，与前两种类型比较，发病较晚，预后较好。

病理甲状腺髓样癌切面呈灰白色或棕褐色，偶然呈红棕色。

甲状腺髓样癌的诊断标准
甲状腺髓样癌的诊断标准主要包括以下几点：
1. 影像学检查：甲状腺超声、甲状腺CT、MRI等影像学检查可以帮助判断肿瘤的位置、大小、形态等，但无法确定癌症的性质。

2. 细针穿刺活检：通过细针穿刺采取组织标本，进行病理学检查，可以明确肿瘤的类型和恶性程度。

3. 免疫组化检测：这是一种能够确定细胞标志物的检测方法，可以帮助判断是否为髓样癌。

4. 术中病理检查：在手术切除病灶的过程中进行病理学检查，可以明确病变的范围和恶性程度。

5. 临床表现：甲状腺髓样癌常常伴随有颈部肿块、淋巴结转移、声音嘶哑等症状，临床表现有助于诊断。

需要指出的是，综合以上多种方法，才能确诊甲状腺髓样癌。

甲状腺髓样癌的诊断与治疗
陈福进;闵华庆
【期刊名称】《国际外科学杂志》
【年(卷),期】1993(8)3
【摘要】甲状腺髓样癌较少见,常易误诊为甲状腺未分化癌。

本病首先由Horn氏于1951年描述,Haz-ard于1959年正式命名为甲状腺髓样癌(Medull-ary Thyroid Carcinoma,简称MTC)。

MTC起源于滤泡旁细胞,又称C细胞的原胺物质摄取和脱羧细胞(amine precussor uptake and dec-arboxylation,简称APUD) 临床上,MTC可分为散发性和家族性,后者为一特殊的常染色体显性遗传性内分泌综合征,属多发性内分泌腺瘤(Mutiple Endocrine Neopl-asia,MEN)并列为MEN Ⅱ型。

【总页数】2页(P134-135)
【作者】陈福进;闵华庆
【作者单位】广州中山医科大学肿瘤医院
【正文语种】中文
【中图分类】R736.1
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2020甲状腺髓样癌诊断与治疗中国专家共识（完整版）甲状腺癌病人中，90%以上为分化型甲状腺癌（differentiated thyroid cancer，DTC），而甲状腺髓样癌（medullary thyroid carcinoma，MTC）的发病率较低，且有其独特的临床病理特征，故而误诊、漏诊和不规范治疗现象仍然普遍存在。

MTC是起源于甲状腺滤泡旁细胞（C细胞）的恶性肿瘤。

C细胞属于APUD系统，具有合成分泌降钙素（calcitonin，Ctn）及降钙素基因相关肽的作用，因此，MTC亦被认为是神经内分泌肿瘤之一。

MTC 在临床分型、诊断、治疗、随访及预后等多个方面与DTC均有所差异，故包括美国甲状腺协会（ATA）在内的多个机构都针对MTC制订了独立的临床诊治指南。

为进一步提高我国MTC的诊治水平并提供更加合理及规范的诊治方案，中国医师协会外科医师分会甲状腺外科医师委员会、中国抗癌协会甲状腺癌专业委员会、中国研究型医院学会甲状腺疾病专业委员会结合近年来MTC领域的最新临床研究成果和国内实际的诊治现状，特制定本共识。

1 MTC的分类及流行病学根据疾病的遗传特性，将MTC分为遗传性和散发性两大类。

几乎所有的遗传性MTC（hereditary medullary thyroid cancer，HMTC）都伴有RET基因的胚系突变，50%的散发性MTC有RET基因的体细胞突变［1］。

散发性MTC发病率较高，占发病总数的75%～80%；遗传性MTC则多以多发性内分泌肿瘤综合征2型（MEN2）中的一部分发病，根据最新的ATA甲状腺髓样癌临床指南描述，可分为多发性内分泌腺瘤2A （MEN2A）和多发性内分泌腺瘤2B（MEN2B）。

1.1 MEN2A 约占所有MEN2病人的95%，又可分为4个亚型。

1.1.1 经典型MEN2A 最为常见，除了MTC外还可并发嗜铬细胞瘤和（或）甲状旁腺功能亢进（hyperparathyroidism，HPTH）。

CEA异常升高首诊的遗传性甲状腺髓样癌家系的临床诊
治和基因突变分析
甲状腺髓样癌（MTC）是一种罕见但具有遗传性的神经内分泌肿瘤。

在临床实践中，通过测量CEA（癌胚抗原）水平可以发现MTC。

本文将探
讨CEA异常升高的首诊遗传性MTC家系的临床诊治和基因突变分析。

临床诊断和治疗：
遗传性MTC通常是由RET基因突变引起的。

因此，在发现CEA异常升
高的患者时，应该考虑进行RET基因突变筛查。

除了测量CEA水平外，还
可以进行超声检查、CT扫描、MRI和核磁共振等影像学检查来评估肿瘤的
位置和大小。

另外，还可以通过活体组织检查或细针穿刺活检确定MTC的
诊断。

一旦诊断为MTC，患者通常需要接受手术治疗，包括全切除甲状腺和
颈部淋巴结清扫。

术后，可以使用血清CEA水平和超声检查来监测患者的
疾病进展和复发。

对于晚期或转移性MTC，还可以考虑放疗、化疗和靶向
治疗等辅助治疗方法。

基因突变分析：
遗传性MTC主要与RET基因突变相关。

研究表明，近70%的遗传性MTC患者中存在RET基因突变。

其中，最常见的突变是由于RET基因外显
子11的C634突变。

此外，还发现了其他一些与MTC相关的基因突变，如MEN2A和MEN2B
病人中的其他RET基因突变，以及SDH基因、PHEO基因和TMEM127基因
突变与MTC的关联。

这些基因突变可能影响甲状腺肿瘤发展的生物学过程。

总结：。

甲状腺髓样癌诊断与治疗中国专家共识甲状腺髓样癌诊断与治疗中国专家共识(2020版)甲状腺癌病人中，90%以上为分化型甲状腺癌(differentiated thyroid cancer，DTC)，而甲状腺髓样癌(medullary thyroid carcinoma，MTC)的发病率较低，且有其独特的临床病理特征，故而误诊、漏诊和不规范治疗现象仍然普遍存在。

MTC是起源于甲状腺滤泡旁细胞(C细胞)的恶性肿瘤。

C 细胞属于APUD系统，具有合成分泌降钙素(calcitonin，Ctn)及降钙素基因相关肽的作用，因此，MTC亦被认为是神经内分泌肿瘤之一。

MTC在临床分型、诊断、治疗、随访及预后等多个方面与DTC均有所差异，故包括美国甲状腺协会(ATA)在内的多个机构都针对MTC制订了独立的临床诊治指南。

为进一步提高我国MTC的诊治水平并提供更加合理及规范的诊治方案，中国医师协会外科医师分会甲状腺外科医师委员会、中国抗癌协会甲状腺癌专业委员会、中国研究型医院学会甲状腺疾病专业委员会结合近年来MTC领域的最新临床研究成果和国内实际的诊治现状，特制定本共识。

1MTC的分类及流行病学根据疾病的遗传特性，将MTC分为遗传性和散发性两大类。

几乎所有的遗传性MTC(hereditary medullary thyroid cancer，HMTC)都伴有RET基因的胚系突变，50%的散发性MTC有RET基因的体细胞突变[1]。

散发性MTC发病率较高，占发病总数的75%~80%;遗传性MTC则多以多发性内分泌肿瘤综合征2型(MEN2)中的一部分发病，根据最新的ATA甲状腺髓样癌临床指南描述，可分为多发性内分泌腺瘤2A(MEN2A)和多发性内分泌腺瘤2B(MEN2B)。

1.1 MEN2A 约占所有MEN2病人的95%，又可分为4个亚型。

1.1.1 经典型MEN2A 最为常见，除了MTC外还可并发嗜铬细胞瘤和(或)甲状旁腺功能亢进(hyperparathyroidism，HPTH)。

甲状腺髓样癌的外科治疗进展邢进;郭京【摘要】Medullary thyroid cancer ( MTC) derives from thyroid parafollicular cells in histology and is a relatively un-common malignant tumor, accounting for 3%~5%of all thyroid carcinomas.MTC cells can produce calcitonin and other endocrine active substances.The clinical manifestations may have diarrhea, flushing and other carcinoid syndrome or endo-crine disorders.Total thyroidectomy is recommended for treatment.So its clinical symptoms and treatments are different from other types of thyroid carcinoma.This article will review the progression in surgical treatment of MTC.%甲状腺髓样癌（ medullary thyroid carcinoma，MTC）为相对少见的恶性肿瘤之一，约占所有甲状腺癌的3％～5％，其组织来源为甲状腺滤泡旁细胞。

MTC细胞能够产生降钙素（ calcitonin）和其他具有内分泌活性的物质，其临床表现可有腹泻、潮红等类癌综合征或内分泌失调的表现，治疗上主张甲状腺全切除术，故不同于其他类型甲状腺癌。

本文就MTC的外科治疗进展作一综述。

【期刊名称】《大连医科大学学报》【年(卷),期】2015(000)001【总页数】4页(P93-96)【关键词】甲状腺肿瘤;髓样癌;手术;进展【作者】邢进;郭京【作者单位】大连市西岗区妇幼保健所，辽宁大连116021;大连医科大学手术学实验中心，辽宁大连116044【正文语种】中文【中图分类】R736.1甲状腺髓样癌(medullary thyroid carcinoma, MTC)是甲状腺癌中相对少见的类型，约占所有甲状腺癌的3%～5%，发病率女性高于男性[1]，其临床表现、诊断及治疗等方面均有异于其他类型的甲状腺癌。