J Pathol Transl Med.  2021 Sep;55(5):307-316. 10.4132/jptm.2021.05.11.

SMARCA4/BRG1 protein-deficient thoracic tumors dictate re-examination of small biopsy reporting in non–small cell lung cancer

• Mehta A
• Bansal D
• Tripathi R
• Jajodia A

• KMID: 2520169
• DOI: http://doi.org/10.4132/jptm.2021.05.11

Abstract

Background
SMARCA4/BRG1 protein–deficient lung adenocarcinomas and thoracic sarcoma are recently described entities that lack distinctive histological features, transcription termination factor 1 (TTF1) reactivity, and actionable driver mutations. The current diagnostic path for small lung biopsies as recommended by the World Health Organization (WHO, 2015) is likely to categorize these as non– small cell carcinoma–not otherwise specified (NSCC-NOS). The present study attempts to define the subtle but distinctive clinicopathologic features of SMARCA4/BRG1 protein-deficient thoracic tumors; highlight their unique biology; and addresses the unmet need to segregate these using a new, tissue-proficient diagnostic pathway.
Methods
All lung biopsies and those from metastatic sites in patients with suspected advanced lung cancer and classified as NSCC-NOS as per WHO (2015) guidelines were subjected to BRG1 testing by immunohistochemistry. SMARCA4/BRG1 protein–deficient thoracic tumors were evaluated by an extended immunohistochemistry panel. Predictive biomarker and programmed death–ligand 1 testing was conducted in all cases.
Results
Of 110 cases, nine were found to be SMARCA4/BRG1 protein-deficient; six were identified as SMARCA4/BRG1 protein–deficient lung adenocarcinomas, and three were SMARCA4/BRG1 protein-deficient thoracic sarcomas. The histology ranged from poorly differentiated to undifferentiated to rhabdoid. None of the cases showed significant expression of TTF1 or p40, and no actionable mutation was identified.
Conclusions
It is difficult to separate BRG1-deficient lung adenocarcinomas and thoracic sarcomas based on morphology alone. We propose a diagnostic pathway for small biopsies of thoracic tumors to segregate these distinct entities so that they can be studied more efficaciously for new biomarkers and therapeutic options.

Keyword

Adenocarcinoma; BRG1 protein; Lung; Non-small cell lung carcinoma

Figure

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  Fig. 1 Axial computed tomography images of SMARCA4/BRG1 protein–deficient thoracic sarcoma (SD-TS). (A) Case No. 7 showed well defined intra-pulmonary mass on the left side, abutting the pleural margin. (B) Case No. 8 showed a well defined heterogeneously enhancing mediastinal-based mass splaying the carina and abutting the right pulmonary artery, encasing the right main bronchus without invasion.

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  Fig. 2 Histology and immunohistochemistry images of SMARCA4/BRG1 protein–deficient lung adenocarcinoma (SD-LUAD). (A) Scanner view of SD-LUAD. Note the solid pattern of growth with a sieved appearance. (B) The dry high-power view exhibits large cells with sharp margins and scattered large signet ring cells that are regularly observed in this tumor type. Also note the bubbly cytoplasm of many cells with indented nuclei. (C) The second case of SD-LUAD exhibited tumor cells arranged in an Indian file pattern. (D) The third case of SD-LUAD showed with highly inflamed background and a solid growth pattern comprised of large rhabdoid cells. (E) Tumor cells showed intra-cytoplasmic mucin (arrow) highlighted by mucicarmine. (F, G) Tumor cells showed strong cytokeratin (CK) and CK7 immunoreactivity, respectively. (H) SD-LUAD expressed BerEp4, supporting the adenocarcinomatous histogenesis. (I) All SD-LUAD expressed varying degrees of Hep Par 1. (J) Transcription termination factor 1 was universally absent. (K, L) No SD-LUAD exhibited BRG1 nuclear expression. Note the strong nuclear reactivity for BRG1 in the inflammatory cells.

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  Fig. 3 Histology images of cases. (A–C) Case No. 8 of SMARCA4/BRG1 protein–deficient thoracic sarcoma (SD-TS) showed a diffuse growth pattern. The constituent cells are large, and some have clear cytoplasm. Nuclei are irregular. (D, E) The stroma is inflamed in SD-TS. (E, F) Two cases (cases No. 7 and 9) revealed tumors with diffuse growth but obvious rhabdoid morphology of spheroidal cytoplasm, eccentric nuclei, and globoid inclusions.

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  Fig. 4 Immunophenotype of SMARCA4/BRG1 protein–deficient thoracic sarcoma (SD-TS). (A) Weak expression of pan-cytokeratin (CK) was observed in all cases of SD-TS. (B) Weak CK7 immunoreactivity was noted in case No. 7. (C) Focal strong CK7 staining is seen in case No. 8. (D) Case No. 7 expressed weak and focal Hep Par 1. (E–G) Expression of stemness markers of SALL4, SOX2, and CD34, respectively. (H) Expression of synaptophysin in case No. 7 of SD-TS. (I) Lack of nuclear expression of BRG1 defining BRG1 loss. Note the intense staining of stromal and inflammatory cells.

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  Fig. 5 Diagnostic schema for SMARCA4/BRG1 protein-deficient thoracic tumors. NSCC-Ad Ca, non-small cell carcinoma adenocarcinoma; SCC, squamous cell carcinoma; IHC, immunohistochemistry; TTF1, transcription termination factor 1; CK, cytokeratin.

Reference

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