Eosinophilic Solid and Cystic (ESC) Renal Cell Carcinomas Harbor TSC Mutations: Molecular Analysis Supports an Expanding Clinicopathologic Spectrum.
Eosinophilic Solid and Cystic (ESC) Renal Cell Carcinomas Harbor TSC Mutations: Molecular Analysis Supports an Expanding Clinicopathologic Spectrum.
复制标题
DOI：
10.1097/pas.0000000000001111
复制
发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Argani P
中科院分区：
文献类型：
--
作者：
Palsgrove DN;Li Y;Pratilas CA;Lin MT;Pallavajjalla A;Gocke C;De Marzo AM;Matoso A;Netto GJ;Epstein JI;Argani P
嗜酸性囊实性(ESC)肾细胞癌(RCC)最近被认为是一种潜在的新亚型肾细胞癌的形态和免疫组织化学特征。这些肿瘤典型地表现为实性和囊性结构，肿瘤细胞含有大量嗜酸性细胞质和颗粒状的细胞质斑点。细胞角蛋白20经常有局部免疫反应。虽然最初的病例都发生在成年女性，结果是良性的，我们最近扩大了这种肿瘤的拟议范围，包括儿科病例、多灶性肿瘤和1例血行转移病例。ESC被认为类似于结节性硬化症患者中一直被发现的RCC的一个亚型，虽然以前的工作已经证明在ESC RCC中TSC1基因的杂合性丢失和TSC2的拷贝数增加，但这些基因在ESC RCC中还没有测序。使用基于捕获和基于扩增的下一代测序，我们现在证明在儿童ESC RCC(9例中的8例)和成人ESC RCC(6例中的6例)中存在一致的TSC1或TSC2基因突变。我们还在一些形态不同的肿瘤中发现了这些突变，从而有可能扩大ESC RCC的范围。其中包括1例成人肾细胞癌，表现为显性的“2型”乳头状肾细胞癌形态，以及3例以前未分类的儿童肾细胞癌中的2例，其特征为ESC肾细胞癌减去颗粒状胞浆斑点。我们还发现了一例具有相同形态和免疫特征的所谓“神经母细胞瘤后嗜酸性肾癌”的TSC突变，提供了后者与ESC肾癌之间的分子联系。总之，ESC肾癌始终存在TSC1或TSC2突变，这在已建立的肾癌亚型中很少见。这些发现支持TSC1/2突变作为ESC肾细胞癌的分子标志物，并提示临床病理范围扩大到包括乳头状结构的肿瘤，偶尔缺乏发育良好的颗粒状细胞质斑点，以及存活神经母细胞瘤患者中具有嗜酸细胞特征的一种亚型肾细胞癌。
Eosinophilic solid and cystic (ESC) renal cell carcinoma (RCC) has recently been described as a potentially new subtype of RCC based upon morphologic and immunohistochemical features. These neoplasms typically demonstrate solid and cystic architecture, and the neoplastic cells contain voluminous eosinophilic cytoplasm with granular cytoplasmic stippling. There is frequently focal immunoreactivity for cytokeratin 20. While the initial cases all occurred in adult females and had benign outcome, we recently expanded the proposed spectrum of this neoplasm to include pediatric cases, multifocal neoplasms, and a case with hematogenous metastasis. ESC has been postulated to be analogous to a subtype of RCC consistently identified in tuberous sclerosis complex patients, and while previous work has demonstrated loss of heterozygosity at the TSC1 locus and copy number gains at TSC2 in ESC RCC, these genes have not been sequenced in ESC RCC. Using capture-based and amplicon-based next generation sequencing, we now demonstrate the consistent presence of either TSC1 or TSC2 gene mutations in pediatric ESC RCC (8 of 9 cases) and adult ESC RCC (6 of 6 cases). We also found these mutations in some neoplasms with variant morphology and thus potentially expand the spectrum of ESC RCC. These include 1 of our adult cases which demonstrated dominant “type 2” papillary RCC morphology and 2 of 3 previously unclassified pediatric RCC with features of ESC RCC minus granular cytoplasmic stippling. We also demonstrate TSC mutations in a case of so-called “oncocytoid RCC after neuroblastoma” with identical morphology and immunoprofile, providing a molecular link between the latter and ESC RCC. In summary, ESC RCC consistently harbors TSC1 or TSC2 mutations, which are infrequently seen in established subtypes of RCC. These findings support TSC1/2 mutation as a molecular marker of ESC RCC, and suggest expansion of the clinicopathologic spectrum to include neoplasms with papillary architecture, occasional cases lacking well-developed granular cytoplasmic stippling, and a subset of RCC with oncocytic features in patients who have survived neuroblastoma.