SMARCA4-deficient pulmonary adenocarcinoma: clinicopathological, immunohistochemical, and molecular characteristics of a novel aggressive neoplasm with a consistent TTF1neg/CK7pos/HepPar-1pos immunophenotype

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.

Frequent loss of claudin‐4 expression in dedifferentiated and undifferentiated endometrial carcinomas

“…More specifically, there were three mutually exclusive patterns of genomic inactivation, resulting in: (i) loss of BRG1 (encoded by SMARCA4 ) expression; (ii) loss of INI1 (encoded by SMARCB1 ) expression; or (iii) concurrent losses of ARID1A and ARID1B expression in the undifferentiated component. This is analogous to what is seen in lung carcinoma and sinonasal carcinoma, in which SWI/SNF inactivation has been reported and is associated with undifferentiated histology as well as aggressive clinical behaviour. Therapeutically, there is accumulating preclinical and early clinical evidence to suggest that tumours that are SWI/SNF‐deficient may be more responsive to drugs that target chromatin remodelling …”

A case report of SMARCA4/BRG1-deficient non-small cell lung cancer with a spindle cell component found by next-generation sequencing of a brain metastasis

“…Regrettably, a de nitive diagnosis required approximately 2 years. The most frequent histology of SMARCA4/BRG1-de cient lung cancer has been reported to be solid adenocarcinoma, large cell carcinoma, and pleomorphic carcinoma with occasional rhabdoid features [6,7,10]. In our case, the major histological pattern was poorly differentiated carcinoma with malignant spindle cells in abundant hyalinous stroma according to the CT-guided needle biopsy; however, these morphological features have been seldom described in articles about SMARCA4/BRG1-de cient NSCLC.…”

“…SMARCA4/BRG1 loss occurs in approximately 4-10% of lung carcinomas, in which the histology was primarily poorly differentiated non-small cell lung carcinoma (NSCLC) including adenocarcinoma, mucinous carcinoma, squamous cell carcinoma, large cell carcinoma, and pleomorphic carcinoma. SMARCA4/BRG-1-de cient has been considered a subset with a heterogeneous spectrum because of its morphological features, such as solid growth and lack of a lepidic pattern; its negativity for thyroid transcription factor 1 (TTF-1) by immunohistochemistry; lack of actionable gene alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) and protooncogene 1 (ROS1) fusions; and poor prognosis [6][7][8][9][10]. However, pathologists might not note the precise diagnosis if they are unable to recognize SMARCA4/BRG-1-de cient NSCLC, including the ability to discriminate this from other SMARCA4/BRG1-de cient thoracic neoplasms represented by SMARCA4de cient thoracic sarcoma.…”

Loss of SWI/SNF complex expression in undifferentiated renal carcinoma in acquired cystic kidney

“…Loss of the SWI/SNF complex has recently been reported in carcinomas of various organs, including stomach, 1 kidneys, 2,3 upper urinary tract, 4 and the lung. 5 These carcinomas exhibited similar morphology, undifferentiated pleomorphic or rhabdoid morphology. For the first time, we report an undifferentiated pleomorphic renal carcinoma that developed in a patient with acquired cystic kidney, showing loss of the SWI/SNF complex.…”

“…Loss of the SWI/SNF complex has recently been reported in carcinomas of various organs, including stomach, kidneys, upper urinary tract, and the lung . These carcinomas exhibited similar morphology, undifferentiated pleomorphic or rhabdoid morphology.…”