Rapidly fatal SMARCA4-deficient undifferentiated sarcoma originating from hybrid hemosiderotic fibrolipomatous tumor/pleomorphic hyalinizing angiectatic tumor of the foot.

Pleomorphic hyalinizing angiectatic tumor (PHAT) of soft parts and hemosiderotic fibrolipomatous tumor (HFLT) are two rare low-grade locally recurring neoplasms with predilection for the foot/ankle. Recent studies support a close link between the two entities, and origin of PHAT from HFLT and occurrence of hybrid HFLT/PHAT have been documented. Both lesions often harbor TGFBR3 or MGEA5 rearrangements. Rare sarcomas originating from HFLT/PHAT have been reported, typically resembling myxofibrosarcoma or myxoinflammatory fibroblastic sarcoma. We describe a novel SMARCA4-deficient undifferentiated sarcoma with rhabdoid features originating from hybrid HFLT/PHAT in the foot of a 54-year-old male. The tumor pursued a highly aggressive course with rapid regrowth after resection and multiple metastases resulting in patient's death within 5 months, despite systemic chemotherapy. Immunohistochemistry revealed SMARCA4 loss in the undifferentiated sarcoma, but not in the HFLT/PHAT. Molecular testing confirmed TGFBR3/MGEA5 rearrangements. This report expands the phenotypes of sarcomas developing from pre-existing PHAT/HFLT.

Deep sequencing of myxoinflammatory fibroblastic sarcoma.

Myxoinflammatory fibroblastic sarcoma (MIFS) has recurrent genetic features in the form of a translocation t(1;10)(p22-31;q24-25), BRAF gene fusions, and/or an amplicon in 3p11-12 including the VGLL3 gene. The breakpoints on chromosomes 1 and 10 in the t(1;10) cluster in or near the TGFBR3 and OGA genes, respectively. We here used a combination of deep sequencing of the genome (WGS), captured sequences (Cap-seq), and transcriptome (RNA-seq) and genomic arrays to investigate the molecular outcome of the t(1;10) and the VGLL3 amplicon, as well as to assess the spectrum of other recurrent genomic features in MIFS. Apart from a ROBO1-BRAF chimera in a t(1;10)-negative MIFS-like tumor, no fusion gene was found at RNA-seq. This was in line with WGS and Cap-seq results, revealing variable breakpoints in chromosomes 1 and 10 and genomic breakpoints that should not yield functional fusion transcripts. The most common genomic rearrangements were breakpoints in or around the OGA, NPM3, and FGF8 genes in chromosome band 10q24, and loss of 1p11-p21 and 10q26-qter (all simultaneously present in 6/7 MIFS); a breakpoint in or near TGFBR3 in chromosome 1 was found in four of these tumors. Amplification and overexpression of VGLL3 was a consistent feature in MIFS and MIFS-like tumors with amplicons in 3p11-12. The significant molecular genetic outcome of the recurrent t(1;10) could be loss of genetic material from 1p and 10q. Other recurrent genomic imbalances in MIFS, such as homozygous loss of CDKN2A and 3p- and 13q-deletions, are shared with other sarcomas, suggesting overlapping pathogenetic pathways.

Soft Tissue Tumors of Uncertain Histogenesis: A Review for Dermatopathologists.

The mesenchymal tumors discussed herein represent a heterogeneous group of neoplasms with distinctive morphologic, immunophenotypic, and molecular genetic features. These uncommon tumors often arise in the dermis and subcutis and can pose a major diagnostic challenge to dermatopathologists because they closely mimic melanoma, carcinoma, fibrous histiocytoma, schwannoma, or granulomatous inflammation. This article reviews the clinical presentation, histopathology, differential diagnosis, and diagnostic pitfalls of epithelioid sarcoma, clear cell sarcoma, perivascular epithelioid cell tumor, ossifying fibromyxoid tumor, pleomorphic hyalinizing angiectatic tumor, and hemosiderotic fibrolipomatous tumor. Associated molecular genetic findings are also briefly reviewed with an emphasis on their diagnostic usefulness.