Thoracic SMARCA2-deficient But SMARCA4-preserved Tumors With Undifferentiated Morphology Combined With Claudin-4 Negativity

Abstract

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently recognized tumor characterized by inactivation of SMARCA4, a SWItch/Sucrose NonFermentable chromatin remodeler, detectable by immunohistochemistry. SMAR-CA4-UT shows undifferentiated or rhabdoid morphology with claudin-4 negativity. However, thoracic undifferentiated tumors with the same histologic features as SMARCA4-UTs but a preserved SMARCA4 expression have so far been underrecognized. We herein report 3 cases of thoracic undifferentiated tumors with isolated loss of SMARCA2 but retained expression of SMARCA4 and SMARCB1. The present tumors were found in 2 men and 1 woman, 40 to 50 years old. All patients were heavy smokers ( ≥ 20 pack-years). The tumors were generally large masses located in the mediastinum, lung > chest wall, or lung and composed of relatively monotonous, round to epithelioid cells with variably rhabdoid cells. Immunohistochemically, the tumors showed claudin-4 negativity with variable expression of cytokeratin. All cases showed highly aggressive clinical behavior with overall survival of 2 to 10 months. These SMARCA2-deficient tumors with preserved SMARCA4 expression appeared to be clinicopathologically indistinguishable from SMARCA4-UTs, except for in their SMARCA4 status. This variant may expand the spectrum of SWItch/Sucrose NonFermentable-deficient undifferentiated tumors of the thoracic region beyond SMARCA4-UT.

Three shades of an unusual mediastinal tumour

“…9 Recently, rare cases of thoracic tumours that are SMARCA4-preserved but SMARCA2-deficient have been described, showing clinicopathologic overlap with thoracic SMARCA4-UTs. 14 In the thoracic cavity, SMARCA4-deficient non-small cell lung carcinoma (SMARCA4d-NSCLC) is a pertinent differential to consider. In this and BRM favours thoracic SMARCA4-UT) 4,15 ; however these were not available in our institution at the time of writing.…”

“…The diagnosis is clinched by loss of BRG (SMARCA4) and BRM (SMARCA2) expression in tumour cells; in some instances, this may be difficult to assess (e.g., highly necrotic limited biopsy samples) 9 . Recently, rare cases of thoracic tumours that are SMARCA4‐preserved but SMARCA2‐deficient have been described, showing clinicopathologic overlap with thoracic SMARCA4‐UTs 14 …”

Clinicopathological and prognostic significance of SWI/SNF complex subunits in undifferentiated gastric carcinoma

“…SCCOHT and thoracic SMARCA4-DUT share similarities in morphologic, immunophenotypic, and molecular features [22,23], further demonstrating that SMARCA4-lost malignancies represent a unique subgroup of tumors with typical morphologic and immunohistochemical features [25]. Immunohistochemical loss of SMARCA2 and SMARCA4 can occur simultaneously or independently, and undifferentiated carcinomas with SMARCA2 loss without SMARCA4 loss have also been reported [26], suggesting that SMARCA2 loss was also involved in the process of tumor dedifferentiation [24]. In this study, SMARCA2 was the most frequently lost subunit, while it was not thoroughly investigated in undifferentiated carcinomas compared with SMARCA4.…”

NUT carcinoma and thoracic SMARCA4‐deficient undifferentiated tumour: facts and controversies

“…69,105,107 A few thoracic undifferentiated tumours with SMARCA2 loss without concomitant SMARCA4 loss have also been documented. 108 Whether SMARCA4 is mutated in such cases is unknown; intact SMARCA4 expression has been rarely reported in SMARCA4-mutant AT/RT and SCCOHT. 109,110 The classification of these neoplasms requires further research.…”

“… 105 SMARCB1 loss is extremely rare in carcinoma in the lung and pleura 69,105,107 . A few thoracic undifferentiated tumours with SMARCA2 loss without concomitant SMARCA4 loss have also been documented 108 . Whether SMARCA4 is mutated in such cases is unknown; intact SMARCA4 expression has been rarely reported in SMARCA4 ‐mutant AT/RT and SCCOHT 109,110 .…”