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Loss of histone H3K27 Trimethylation (H3K27me3) immunohistochemical expression is commonly used as an ancillary test and a surrogate marker for the diagnosis of malignant peripheral nerve sheath tumor (MPNST). A potential histological mimic of MPNST is sarcomatoid carcinoma. Prompted by an index specimen of sarcomatoid carcinoma with H3K27me3 loss and the lack of literature on such phenomenon, we sought to determine the frequency of H3K27me3 loss of expression in a cohort of sarcomatoid carcinomas. Fifty specimens of primary and metastatic sarcomatoid carcinomas with spindle cell morphology mimicking MPNST were prospectively and retrospectively retrieved from our institutional archives and stained with an antibody to H3K27me3. H3K27me3 staining was lost in 4 of the 50 specimens (8%). These specimens included a primary sarcomatoid urothelial carcinoma of the bladder resection, two local recurrences (sarcomatoid squamous cell carcinoma of the larynx and oral cavity) as well as a metastatic sarcomatoid renal cell carcinoma. Next-generation sequencing performed on all four specimens demonstrated gene mutations and copy number alterations with TP53, FANC (FANCD2 and FANCI), and TERT being the most common gene mutations and CDKN2A/B copy number loss and 11q region amplification being the most common copy number gene alterations. Mutations involving NF1, SUZ12, or EED were absent in all tested specimens. In conclusion, H3K27me3 expression may be lost in as many as 8% of sarcomatoid carcinomas which can pose as a potential diagnostic pitfall, especially in challenging sarcomatoid carcinoma specimens with absent keratin staining. [ABSTRACT FROM AUTHOR]