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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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Abstract

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.

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Authors and Affiliations

  1. Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital of Erlangen, Erlangen, Germany

    Abbas Agaimy, Evgeny A. Moskalev, Arndt Hartmann & Florian Haller

  2. Department of Internal Medicine-1, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital of Erlangen, Erlangen, Germany

    Florian Fuchs

  3. Section of Thoracic Surgery, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital of Erlangen, Erlangen, Germany

    Horia Sirbu

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  1. Abbas Agaimy
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  2. Florian Fuchs
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  4. Horia Sirbu
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Correspondence to Abbas Agaimy.

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The authors confirm that the study has been performed in accordance with accepted principles of ethical and professional conduct for biomedical scientific research. The study is covered by ethical vota of the medical faculty of the University of Erlangen for retrospective translational research activities.

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The authors declare that they have no conflicts of interest.

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Agaimy, A., Fuchs, F., Moskalev, E.A. et al. SMARCA4-deficient pulmonary adenocarcinoma: clinicopathological, immunohistochemical, and molecular characteristics of a novel aggressive neoplasm with a consistent TTF1neg/CK7pos/HepPar-1pos immunophenotype. Virchows Arch 471, 599–609 (2017). https://doi.org/10.1007/s00428-017-2148-5

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  • DOI: https://doi.org/10.1007/s00428-017-2148-5

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