SMARCA4-deficient pulmonary adenocarcinoma: clinicopathological, immunohistochemical, and molecular characteristics of a novel aggressive neoplasm with a consistent TTF1neg/CK7pos/HepPar-1pos immunophenotype
SMARCA4-deficient pulmonary adenocarcinoma: clinicopathological, immunohistochemical, and molecular characteristics of a novel aggressive neoplasm with a consistent TTF1neg/CK7pos/HepPar-1pos immunophenotype
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DOI：
10.1007/s00428-017-2148-5
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发表时间：
2017-11-01
期刊：
影响因子：
3.5
通讯作者：
Haller, Florian
中科院分区：
文献类型：
--
作者：
Agaimy, Abbas;Fuchs, Florian;Haller, Florian
SMARCA4 是染色质重塑开关蔗糖不可发酵 (SWI/SNF) 复合物的成员，它的改变是非小细胞肺癌 (NSCLC) 亚型的特征，但缺乏对该肿瘤类型的详细形态学和免疫表型描述。我们描述了通过免疫组织化学 (IHC) 常规筛查发现不表达 SMARCA4 的 20 例 NSCLC 病例。使用 160 个癌症相关基因组（包括 SMARCA4 的完整编码序列）对这些肿瘤进行 CK7、TTF1、SMARCA2、SMARCA4、SMARCB1 和 HepPar-1 染色，并分析分子变化。患者包括 8 名女性和 12 名男性，年龄在 41 至 76 岁之间（中位数为 60 岁）。在 18 个有详细数据的肿瘤中，14 个出现同步远处转移 (M1)。组织学检查主要显示实性腺癌 (n = 15)、横纹肌样癌 (n = 3) 和粘液性腺癌 (n = 2)。除横纹肌样病例外，所有肿瘤均至少显示局灶性明确腺体，且缺乏鳞状分化，证明腺癌的诊断是合理的。 IHC 在 18/20 例中显示出独特的统一免疫表型（CK7（+）/HepPar-1（+）/TTF1（-））。仅2/16病例表现出神经内分泌标志物有限的弱表达。在所有检查病例中均未发现 EGFR 突变以及 EML4-ALK 和 ROS1 基因重排。使用 160 个癌症相关基因组进行的下一代测序显示，在 12 例成功测试的病例中，有 9 例 (75%) 存在 SMARCA4 和 TP53 并发突变。我们的研究强调（1）SMARCA4 缺陷型肺腺癌的形态多样性，（2）在 HepPar-1 表达存在的情况下，TTF1 始终不表达，（3）不存在 EGFR 驱动突变，以及（4）频繁的失活 SMARCA4 突变是观察到的 SMARCA4 蛋白丢失的潜在机制。 SMARCA4 缺陷型肺腺癌正在成为 TTF1 阴性 NSCLC 中一种独特但表型异质的分子亚组。该 NSCLC 亚型中一致的 HepPar-1 表达可能是一个诊断陷阱，值得进一步研究以探索所涉及的机制。
Alterations in SMARCA4, a member of the chromatin remodeling Switch Sucrose Non-Fermentable (SWI/SNF) complex, characterize a subset of non-small cell lung cancer (NSCLC), but detailed morphological and immunophenotypic description of this tumor type is lacking. We describe 20 NSCLC cases found on routine screening not to express SMARCA4 by immunohistochemistry (IHC). These tumors were stained for CK7, TTF1, SMARCA2, SMARCA4, SMARCB1, and HepPar-1 and analyzed for molecular alterations, using a 160 cancer-related gene panel including the full coding sequence of SMARCA4. Patients were eight females and 12 males aged 41 to 76 (median, 60). Of 18 tumors with detailed data, 14 presented with synchronous distant metastases (M1). Histological examination showed predominantly solid adenocarcinoma (n = 15), frankly rhabdoid (n = 3) and mucinous (n = 2) patterns. Except for the rhabdoid cases, all tumors showed at least focal unequivocal glands and lacked squamous differentiation, justifying a diagnosis of adenocarcinoma. IHC showed a distinctive uniform immunophenotype (CK7(+)/HepPar-1(+)/TTF1(-)) in 18/20 cases. Only 2/16 cases showed limited weak expression of neuroendocrine markers. EGFR mutations and EML4-ALK and ROS1 gene rearrangements were not found in any of the examined cases. Next-generation sequencing, using a 160 cancer-related gene panel, revealed concurrent SMARCA4 and TP53 mutations in nine of the 12 (75%) successfully tested cases. Our study highlights (1) the morphological diversity of SMARCA4-deficient lung adenocarcinoma, (2) the consistent absence of expression of TTF1 in the presence of expression of HepPar-1, (3) absence of EGFR driver mutations, and (4) frequent inactivating SMARCA4 mutations as underlying mechanism of the observed SMARCA4 protein loss. SMARCA4-deficient pulmonary adenocarcinoma is emerging as a distinctive, albeit phenotypically heterogeneous molecular subgroup of TTF1-negative NSCLC. Uniform HepPar-1 expression in this subset of NSCLC may represent a diagnostic pitfall and merits further studies to explore the mechanisms involved.