Comprehensive Molecular Profiling of Sinonasal Teratocarcinosarcoma Highlights Recurrent SMARCA4 Inactivation and CTNNB1 Mutations

Abstract

Sinonasal teratocarcinosarcoma (TCS) is a rare tumor defined by intermixed neuroepithelial, mesenchymal, and epithelial elements. While its etiology was historically ambiguous, we recently reported frequent SMARCA4 loss by immunohistochemistry, suggesting that TCS might be related to SMARCA4-deficient sinonasal carcinomas. However, other molecular alterations including CTNNB1 mutation have been reported in TCS, and its full genetic underpinnings are unclear. Here, we performed the first comprehensive molecular analysis of sinonasal TCS to better understand its pathogenesis and classification. We collected 30 TCS including 22 cases from our initial study. Immunohistochemical loss of SMARCA4 was seen in 22 cases (73%), with total loss in 18 cases (60%). β-catenin showed nuclear localization in 14 cases (64%) of the subset tested. We selected 17 TCS for next-generation sequencing with enrichment for partial or intact SMARCA4 immunoexpression. We identified inactivating SMARCA4 mutations in 11 cases (65%) and activating CTNNB1 mutations in 6 cases (35%), including 5 cases with both. Of 5 cases that lacked SMARCA4 or CTNNB1 mutation, 2 harbored other SWI/SNF complex and Wnt pathway alterations, including 1 with SMARCB1 inactivation and 1 with concomitant APC and ARID1A mutations, and 3 had other findings, including DICER1 hotspot mutation. These findings confirm that SMARCA4 inactivation is the dominant genetic event in sinonasal TCS with frequent simultaneous CTNNB1 mutations. They further underscore a possible relationship between TCS and sinonasal carcinomas with neuroendocrine/neuroectodermal differentiation. However, while SMARCA4 and β-catenin immunohistochemistry may help confirm a challenging diagnosis, TCS should not be regarded as a molecularly defined entity.

Fine needle aspiration cytology of metastatic SMARCA4‐deficient sinonasal teratocarcinosarcoma: First report in literature

“…However, loss of BRG1 protein encoded by SMARCA4 is seen across all the components 2,5 . Nuclear positivity for β‐catenin may be seen in some cases 5,7 . The SWI/SNF complex regulates expression of the Wnt/β‐catenin pathway, and concomitant inactivating SMARCA4 and activating CTNNB1 mutations have been described, 7,8 explaining the presence of β‐catenin immunopositivity.…”

“…Nuclear positivity for β‐catenin may be seen in some cases 5,7 . The SWI/SNF complex regulates expression of the Wnt/β‐catenin pathway, and concomitant inactivating SMARCA4 and activating CTNNB1 mutations have been described, 7,8 explaining the presence of β‐catenin immunopositivity. Role of the SWI/SNF pathway in pathogenesis of TCS also has therapeutic implications, with the role of EZH2 inhibitors and immunotherapy being explored.…”

Teratocarcinosarcoma of the head and neck: Clinicopathologic review of a rare entity

“…Recently, immunohistochemical analysis of TCSs has revealed frequent loss of SMARCA4 (BRG1) protein expression in a majority (73% to 82%) of cases, with complete loss of nuclear staining across all tumor components in 60% to 68%, and partial/heterogenous loss in 14% of cases. 19,26,29,30 SMARCA4 is a component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex that regulates the vital processes of cell proliferation and differentiation. 26 This marker may provide a useful and reliable diagnostic tool to confirm the challenging diagnosis of TCS in limited biopsy samples, particularly considering that SMARCA4 is intact in all other poorly differentiated sinonasal carcinomas and neuroendocrine tumors of the head and neck.…”

“…25 In contrast to SALL-4 immunoexpression, β-catenin is overexpressed with significant nuclear localization, predominantly in the mesenchymal component but only in a subset of TCSs. 19,25,30,32 Although approximately 83% of TCSs are positive for NKX2.2, its utility is limited when differentiating TCS from sinonasal tumors showing small round blue cell morphology, including Ewing sarcoma, melanoma, olfactory neuroblastoma, and small cell carcinoma. However, it may be useful to distinguish TCS from other sinonasal malignancies that do not express NKX2.2, including sinonasal undifferentiated carcinoma, SMARCB1-deficient carcinoma, and NUT carcinomas.…”

“…9,19,29–32 Another, but less common, genetic abnormality in TCS is a somatic CTNNB1 (β-catenin) gene activating point mutation (p.S45F codon), which has been reported in 35% of studied cases. 30,32 This provides useful insights into the potential genetic driver mutations of TCS, particularly when considering that both the SWI/SNF complex and Wnt/β-catenin pathway are implicated in the tumorigenesis of this neoplasm. Other less frequent genetic alterations that may have a role in TCS molecular pathways involve other members of the SWI/SNF family and the Wnt/β-catenin pathway.…”