LAUSR

SMARCB1-deficient sinonasal carcinoma (SNC) is an aggressive malignancy characterized by INI1 loss mostly due to homozygous SMARCB1 deletion. With the exception of a few reported cases, these tumors have not been thoroughly studied by massive parallel sequencing (MPS). A retrospective cohort of 22 SMARCB1-deficient SNC were studied by light microscopy, immunohistochemistry, FISH (n=9), targeted exome MPS (n=12) and by FACETS (n=10), a bioinformatics pipeline for copy number/zygosity assessment. SMARCB1-deficient SNC was found in 13 (59%) men and 9 (41%) women. Most common growth patterns were basaloid (59%), occurring mostly in men (77%) and plasmacytoid/eosinophilic/rhabdoid pattern (23%), arising mostly in women (80%). The former group was significantly younger (median age 46 years, range 24-54, vs 79 years, range 66-95, p<0.0001). Clear cell, pseudoglandular, glandular, spindle cell and sarcomatoid features were variably present. SMARCB1-deficient SNC expressed cytokeratin (100%), p63 (72%), neuroendocrine markers (52%), CDX-2 (44%), S-100 (25%), CEA (4/4 cases), Hepatocyte (2/2 cases), and aberrant nuclear ß-catenin (1/1 case). SMARCB1 showed homozygous deletion (68%), hemizygous deletion (16%) or truncating mutations associated with copy neutral-loss of heterozygosity (11%). Co-existing genetic alterations were 22q loss including loss of NF2 and CHEK2 (50%), chromosome 7 gain (25%), and TP53 V157F, CDKN2A W110* and CTNNB1 S45F mutations. At 2-years and 5-years, the disease-specific survival and disease-free survival were 70% and 35%, and 13% and 0%, respectively. SMARCB1-deficient SNC is phenotypically and genetically diverse and these distinctions warrant further investigation for their biological and clinical significance.