SMARCB1-deficient Tumors of Childhood: A Practical Guide

Abstract

The SMARCB1 gene ( INI1, BAF47) is a member of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, involved in the epigenetic regulation of gene transcription. SMARCB1 acts as a tumor suppressor gene, and loss of function of both alleles gives rise to SMARCB1-deficient tumors. The prototypical SMARCB1-deficient tumor is the malignant rhabdoid tumor (MRT) which was first described in the kidney but also occurs in soft tissue, viscera, and the brain (where it is referred to as atypical teratoid rhabdoid tumor or AT/RT). These are overwhelmingly tumors of the very young, and most follow an aggressive and ultimately lethal course. Morphologically, most but not all contain a population of "rhabdoid" cells, which are large cells with abundant cytoplasm, perinuclear spherical inclusions, and eccentric vesicular nuclei with large inclusion-like nucleoli. MRT immunohistochemistry reveals complete loss of SMARCB1 nuclear expression, and molecular analysis confirms biallelic SMARCB1 inactivation in the vast majority. Rare AT/RTs have loss of SMARCA4, another SWI/SNF member, rather than SMARCB1. With the widespread adoption of SMARCB1 immunohistochemistry, an increasing number of SMARCB1-deficient tumors outside of the MRT-AT/RT spectrum have been described. In addition to MRT and AT/RT, pediatric tumors with complete loss of SMARCB1 expression include cribriform neuroepithelial tumor, renal medullary carcinoma, and epithelioid sarcoma. Tumors with variable loss of SMARCB1 expression include subsets of epithelioid malignant peripheral nerve sheath tumor, schwannomas arising in schwannomatosis, subsets of chordomas, myoepithelial carcinomas, and sinonasal carcinomas. Variable and reduced expression of SMARCB1 is characteristic of synovial sarcoma. In this review, the historical background, clinical characteristics, morphology, immunohistochemical features, and molecular genetics most germane to these tumors are summarized. In addition, familial occurrence of these tumors (the rhabdoid tumor predisposition syndrome) is discussed. It is hoped that this review may provide practical guidance to pathologists encountering tumors that have altered expression of SMARCB1.

Cytopathologic features of SMARCB1 (INI‐1)‐deficient sinonasal carcinoma

“…Other malignancies in which INI‐1 inactivation has been found include pediatric atypical teratoid/rhabdoid tumor, epithelioid sarcoma, renal medullary carcinoma, rhabdoid tumors of the kidney and soft tissue, myoepithelial carcinoma of the soft tissue, epithelioid malignant peripheral nerve sheath tumor, and extraskeletal myxoid chondrosarcoma. These entities usually occur in young patients, have rhabdoid morphology, and are aggressive malignancies with poor prognoses . Although the clinical course and appearance of these malignancies may be similar to those of IDSNC, the disparate age at the time of presentation and the location of the primary tumor make it unlikely that they would raise a diagnostic dilemma.…”

“…These entities usually occur in young patients, have rhabdoid morphology, and are aggressive malignancies with poor prognoses. 9 Although the clinical course and appearance of these malignancies may be similar to those of IDSNC, the disparate age at the time of presentation and the location of the primary tumor make it unlikely that they would raise a diagnostic dilemma. Myoepithelial carcinoma may present the only other INI-1-deficient malignancy that could occur primarily in the head and neck region of an adult, and this entity would be distinguished from IDSNC by myoepithelial marker expression as mentioned above.…”

A BAFfling liver aspirate: Metastatic high grade SMARCA4 deficient undifferentiated gastroesophageal junction carcinoma masquerading as a hematolymphoid malignancy

“…Some of these undifferentiated tumors belong to a recently delineated group of neoplasms related to abnormalities in genes of the Switch/Sucrose non-fermenting (SWI/SNF) chromatin remodeling complex, the mammalian counterpart of which is referred to as BAF (BRG1/BRM associated factors). The best known of these "BAF-altered family of tumors" 2 are malignant rhabdoid tumors 3,4 characterized by the loss of SMARCB1 (INI1) and small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) characterized by SMARCA4 mutations resulting in the loss of BRG1 protein. 5 We herein report a case of high grade undifferentiated SMARCA4-deficient gastroesophageal junction carcinoma metastatic to the liver diagnosed by FNA, after being initially interpreted as a hematolymphoid neoplasm.…”

A case of malignant rhabdoid tumor mimicking yolk sac tumor

“…MRT has occasionally been misdiagnosed as another tumor or as an infectious disease because it sometimes does not have a rhabdoid appearance. Thus, MRTs without a rhabdoid appearance might as well be described as SMARCB1‐deficient tumors (SDTs), especially in children older than three years . However, as prototypical SDTs in children are MRTs, childhood SDTs are often described as MRTs even in the case of lacking a rhabdoid appearance.…”

“…Thus, MRTs without a rhabdoid appearance might as well be described as SMARCB1-deficient tumors (SDTs), especially in children older than three years. 13 However, as prototypical SDTs in children are MRTs, childhood SDTs are often described as MRTs even in the case of lacking a rhabdoid appearance. The very rare occurrence of extracranial and extrarenal MRTs may have been a factor leading to our misdiagnosis.…”