van Treijen Mark J.C., de Vries Lisa H., Hertog Doenja, Vriens Menno R., Verrijn Stuart Annemarie A., van Nesselrooij Bernadette P.M., Valk Gerlof D.
Endocrinologist, Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
Multiple Endocrine Neoplasia (MEN) type 2 A and B are rare autosomal dominant inherited cancer syndromes characterized by tumors of the C cells of the thyroid, of the adrenal medulla, and parathyroid glands. MEN2 is caused by a genetic defect in the REarranged during Transfection (RET) proto-oncogene on chromosome 10 (10q11-2), leading to a ligand-independent activation of the transmembrane RET receptor tyrosine kinase and consequently its intra-cellular pathways. Different mutations lead to different levels of activation and MEN2 is therefore characterized by a strong genotype-phenotype correlation. Nearly all patients with MEN2A have either C-cell hyperplasia (CCH) or medullary thyroid cancer (MTC), 50% have pheochromocytoma (PHEO), and 20-30% hyperparathyroidism (pHPT) but incidence of these manifestations is depending on the underlying RET mutation. Patients with MEN2B have a 100% incidence of CCH or MTC, PHEO in 30-50%, mucosal neuromas, and rarely pHPT. Endocrine tumors in MEN2 are often multifocal and bilateral. Nowadays, the diagnosis of MEN2 is made by genetic testing. After diagnosis, annual screening for associated manifestations and prophylactic thyroidectomy for preventing metastasized MTC are advised. Optimal age for preventive surgery or when to start screening for each manifestation is based upon the underlying RET mutation. In patients with MTC present at diagnosis, adequate staging is needed before surgical resection, since surgery is the only curative treatment. The most important biomarker for MTC is calcitonin. Fractionated metanephrines are used for early diagnosing PHEO and calcium and PTH for hyperparathyroidism. For PHEO, a minimal invasive surgical resection is recommended. In pHPT the surgical approach should be tailored to the amount and location of the enlarged glands visualized with imaging. Recurrent MTC requires physical examination, neck ultrasound, and measurement of serum calcitonin and carcinoembryonic antigen (CEA) levels every 6 months. For metastasized MTC, treatment can be successful with multikinase inhibitors (vandetanib, cabozantinib) and selective RET inhibitors (pralsetinib, selpercatinib). For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.
多发性内分泌腺瘤（MEN）2 A型和B型是罕见的常染色体显性遗传癌症综合征，其特征是甲状腺C细胞、肾上腺髓质和甲状旁腺发生肿瘤。MEN2是由10号染色体（10q11-2）上转染期间重排（RET）原癌基因的遗传缺陷引起的，导致跨膜RET受体酪氨酸激酶的配体非依赖性激活，进而激活其细胞内信号通路。不同的突变导致不同程度的激活，因此MEN2具有很强的基因型-表型相关性。几乎所有MEN2A患者都有C细胞增生（CCH）或甲状腺髓样癌（MTC），50%有嗜铬细胞瘤（PHEO），20-30%有甲状旁腺功能亢进（pHPT），但这些表现的发生率取决于潜在的RET突变。MEN2B患者CCH或MTC的发生率为100%，PHEO为30-50%，有黏膜神经瘤，很少有pHPT。MEN2中的内分泌肿瘤通常是多灶性和双侧性的。如今，MEN2的诊断通过基因检测进行。诊断后，建议每年筛查相关表现，并进行预防性甲状腺切除术以预防转移性MTC。预防性手术的最佳年龄或何时开始筛查每种表现取决于潜在的RET突变。对于诊断时已存在MTC的患者，手术切除前需要进行充分的分期，因为手术是唯一的治愈性治疗方法。MTC最重要的生物标志物是降钙素。分段甲氧基肾上腺素用于早期诊断PHEO，钙和甲状旁腺激素用于诊断甲状旁腺功能亢进。对于PHEO，建议进行微创外科切除。对于pHPT，手术方法应根据影像学显示的增大腺体的数量和位置进行调整。复发性MTC需要每6个月进行体格检查、颈部超声检查以及测量血清降钙素和癌胚抗原（CEA）水平。对于转移性MTC，使用多激酶抑制剂（凡德他尼、卡博替尼）和选择性RET抑制剂（普拉替尼、塞尔帕替尼）治疗可能会取得成功。欲全面涵盖内分泌学的所有相关领域，请访问我们的在线免费网络文本，网址为WWW.ENDOTEXT.ORG。
