Elisei Rossella, Cosci Barbara, Romei Cristina, Bottici Valeria, Renzini Giulia, Molinaro Eleonora, Agate Laura, Vivaldi Agnese, Faviana Pinuccia, Basolo Fulvio, Miccoli Paolo, Berti Piero, Pacini Furio, Pinchera Aldo
Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy.
J Clin Endocrinol Metab. 2008 Mar;93(3):682-7. doi: 10.1210/jc.2007-1714. Epub 2007 Dec 11.
Medullary thyroid carcinoma (MTC) is a well-differentiated thyroid tumor that maintains the typical features of C cells. An advanced stage and the presence of lymph node metastases at diagnosis have been demonstrated to be the most important bad prognostic factors. Somatic RET mutations have been found in 40-50% of MTCs. Although a relationship between somatic mutations and bad prognosis has been described, data are controversial and have been performed in small series with short-term follow ups. The aim of this study was to verify the prognostic value of somatic RET mutations in a large series of MTCs with a long follow up.
We studied 100 sporadic MTC patients with a 10.2 yr mean follow-up. RET gene exons 10-11 and 13-16 were analyzed. The correlation between the presence/absence of a somatic RET mutation, clinical/pathological features, and outcome of MTC patients was evaluated.
A somatic RET mutation was found in 43 of 100 (43%) sporadic MTCs. The most frequent mutation (34 of 43, 79%) was M918T. RET mutation occurrence was more frequent in larger tumors (P=0.03), and in MTC with node and distant metastases (P<0.0001 and P=0.02, respectively), thus, a significant correlation was found with a more advanced stage at diagnosis (P=0.004). A worse outcome was also significantly correlated with the presence of a somatic RET mutation (P=0.002). Among all prognostic factors found to be correlated with a worse outcome, at multivariate analysis only the advanced stage at diagnosis and the presence of a RET mutation showed an independent correlation (P<0.0001 and P=0.01, respectively). Finally, the survival curves of MTC patients showed a significantly lower percentage of surviving patients in the group with RET mutations (P=0.006).
We demonstrated that the presence of a somatic RET mutation correlates with a worse outcome of MTC patients, not only for the highest probability to have persistence of the disease, but also for a lower survival rate in a long-term follow up. More interestingly, the presence of a somatic RET mutation correlates with the presence of lymph node metastases at diagnosis, which is a known bad prognostic factor for the definitive cure of MTC patients.
甲状腺髓样癌（MTC）是一种分化良好的甲状腺肿瘤，保留了C细胞的典型特征。已证实诊断时处于晚期和存在淋巴结转移是最重要的不良预后因素。在40%-50%的MTC中发现了体细胞RET突变。尽管已经描述了体细胞突变与不良预后之间的关系，但数据存在争议，且这些研究是在小样本系列且随访时间较短的情况下进行的。本研究的目的是在一大系列长期随访的MTC中验证体细胞RET突变的预后价值。
我们研究了100例散发性MTC患者，平均随访10.2年。分析了RET基因的第10-11外显子和第13-16外显子。评估了体细胞RET突变的有无、临床/病理特征与MTC患者预后之间的相关性。
100例散发性MTC中有43例（43%）发现体细胞RET突变。最常见的突变（43例中的34例，79%）是M918T。RET突变在较大肿瘤中更常见（P=0.03），在伴有淋巴结和远处转移的MTC中更常见（分别为P<0.0001和P=0.02），因此，与诊断时更晚期显著相关（P=0.004）。体细胞RET突变的存在也与更差的预后显著相关（P=0.002）。在所有与更差预后相关的预后因素中，多变量分析显示只有诊断时的晚期和RET突变的存在显示出独立相关性（分别为P<0.0001和P=0.01）。最后，MTC患者的生存曲线显示RET突变组的存活患者百分比显著更低（P=0.006）。
我们证明体细胞RET突变的存在与MTC患者更差的预后相关，不仅因为疾病持续存在的可能性最高，还因为长期随访中的生存率更低。更有趣的是，体细胞RET突变的存在与诊断时淋巴结转移的存在相关，而淋巴结转移是MTC患者根治的已知不良预后因素。
