Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale, Marseille Medical Genetics, Marseille, France; Assistance Publique-Hôpitaux de Marseille, Department of Endocrinology, Hôpital de la Conception, Centre de Référence des Maladies Rares de l'hypophyse, Marseille, France.
Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lancet Diabetes Endocrinol. 2019 Mar;7(3):213-220. doi: 10.1016/S2213-8587(18)30336-X. Epub 2019 Jan 16.
Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection.
This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features.
345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs.
Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year.
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多发性内分泌肿瘤 2B 型是一种主要由 Met918Thr 种系 RET 突变引起的罕见综合征，其特征为甲状腺髓样癌、嗜铬细胞瘤和内分泌外特征。关于多发性内分泌肿瘤 2B 型的自然病史数据很少。我们旨在深入了解多发性内分泌肿瘤 2B 型的表型和自然病史，提高认识并改善检测。
这是一项回顾性、多中心、国际性研究，研究对象为携带 Met918Thr RET 变异体且无年龄限制的患者。该研究是在全球 48 个中心的注册数据中进行的。从 1970 年至 2016 年随访的患者的数据从 2016 年 5 月 1 日至 2018 年 5 月 31 日检索。我们的主要目标是确定总体生存率和甲状腺髓样癌特异性生存率，依据是患者是否在 1 岁之前进行了早期甲状腺切除术。我们还评估了甲状腺髓样癌的缓解情况、嗜铬细胞瘤的发生率和治疗情况，以及内分泌外特征的外显率。
共纳入 345 例患者，其中 338 例（98%）接受了甲状腺切除术。在总共 345 例患者中，有 71 例（21%）在中位年龄为 25 岁（范围 <1-59）时死亡。在 20 例患者中，甲状腺切除术在 1 岁之前完成，其中 18 例（15 例，83%）患者（2 例患者死于与甲状腺髓样癌无关的原因）长期缓解（即降钙素水平无法检测到）。在接受甲状腺切除术的患者中，生存曲线在 1 岁之前或之后之间没有显示出任何显著差异（对数秩检验比较生存曲线：p=0.2；风险比 0.35；95%CI 0.07-1.74）。然而，在 1 岁之前和之后接受甲状腺切除术的患者的缓解状态之间存在显著差异（p<0.0001）。在其他 318 例 1 岁后接受甲状腺切除术的患者中，318 例患者中有 47 例（15%）获得了生化和结构缓解。在 313 例患者中，通过 28 岁时的检测诊断出双侧嗜铬细胞瘤在 156 例（50%）患者中。在 31 例患者中进行了肾上腺保留手术：在 31 例患者中有 3 例（10%）发生长期复发，而 16 例（62%）患者获得了正常的肾上腺功能。所有有可用数据的患者（n=287）至少有一个内分泌外特征，包括 190 例患者中有 106 例（56%）表现出马凡体型体态、黏膜神经瘤和胃肠道迹象。
在 1 岁之前完成的甲状腺切除术与高治愈率相关。现实情况是，大多数患有该综合征的儿童将在推荐年龄之后被诊断。在多发性内分泌肿瘤 2B 型中，可行肾上腺保留手术，并有获得正常肾上腺功能的良好机会。为了改善此类患者的预后，必须让每一位医疗保健提供者都意识到这种罕见综合征的内分泌外症状和自然病史。这项研究的意义包括提高对内分泌外症状的认识，以及建议在 1 岁之前进行甲状腺切除术。
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