Agaimy Abbas, Fuchs Florian, Moskalev Evgeny A, Sirbu Horia, Hartmann Arndt, Haller Florian
Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital of Erlangen, Erlangen, Germany.
Department of Internal Medicine-1, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital of Erlangen, Erlangen, Germany.
Virchows Arch. 2017 Nov;471(5):599-609. doi: 10.1007/s00428-017-2148-5. Epub 2017 May 30.
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.
染色质重塑开关蔗糖非发酵（SWI/SNF）复合体成员SMARCA4的改变是一部分非小细胞肺癌（NSCLC）的特征，但缺乏对这种肿瘤类型详细的形态学和免疫表型描述。我们描述了20例在常规筛查中通过免疫组织化学（IHC）检测发现不表达SMARCA4的NSCLC病例。这些肿瘤进行了CK7、TTF1、SMARCA2、SMARCA4、SMARCB1和HepPar-1染色，并使用包括SMARCA4完整编码序列在内的160个癌症相关基因panel分析分子改变。患者为8名女性和12名男性，年龄41至76岁（中位数为60岁）。在18例有详细数据的肿瘤中，14例伴有同步远处转移（M1）。组织学检查显示主要为实性腺癌（n = 15）、明显的横纹肌样（n = 3）和黏液样（n = 2）模式。除横纹肌样病例外，所有肿瘤均显示至少局灶性明确的腺管结构且缺乏鳞状分化，符合腺癌诊断。IHC显示18/20例具有独特的一致免疫表型（CK7/HepPar-1/TTF1）。仅2/16例显示神经内分泌标志物有限的弱表达。在所检查的病例中均未发现EGFR突变以及EML4-ALK和ROS1基因重排。使用160个癌症相关基因panel进行的二代测序显示，在12例成功检测的病例中有9例（75%）同时存在SMARCA4和TP53突变。我们的研究强调了（1）SMARCA4缺陷型肺腺癌的形态学多样性，（2）在HepPar-1表达存在的情况下TTF1表达持续缺失，（3）不存在EGFR驱动突变，以及（4）频繁的SMARCA4失活突变是观察到的SMARCA4蛋白缺失的潜在机制。SMARCA4缺陷型肺腺癌正在成为一种独特的、尽管表型异质性的TTF1阴性NSCLC分子亚组。NSCLC这一亚组中一致的HepPar-1表达可能代表一个诊断陷阱，并值得进一步研究以探索其中涉及的机制。
