ZFTA::RELA fusion in a distinct liposarcoma morphologically overlapping with chondroid lipoma

Abstract

Chondroid lipoma is a rare benign adipose tumor characterized by a recurrent ZFTA::MRTFB fusion. Herein, we report an unusual liposarcoma that partly exhibited overlapping features with those of chondroid lipoma and harbored a ZFTA::RELA fusion. A 59‐year‐old man presented with a shoulder mass that had existed for approximately 8 years and with increasing pain due to a pelvic mass. The 5.8‐cm resected shoulder tumor partly consisted of nests and strands of variably lipogenic epithelioid cells within a hyalinized or focally chondromyxoid stroma, indistinguishable from chondroid lipoma. The histological pattern gradually transitioned to highly cellular, stroma‐poor, diffuse sheets of cells with greater nuclear atypia and mitotic activity. Vascular invasion and necrosis were present. The metastatic pelvic tumor revealed a similar histology. Despite multimodal treatment, the patient developed multiple bone metastases and succumbed to the disease 14 months after presentation. Targeted RNA sequencing identified an in‐frame ZFTA (exon 3)::RELA (exon 2) fusion, which was confirmed by reverse transcription‐polymerase chain reaction, Sanger sequencing, and break‐apart fluorescent in situ hybridization assays. The tumor showed a different histology from that of ependymoma, no brain involvement, and no match with any sarcoma types or ZFTA::RELA‐positive ependymomas according to DNA methylation analysis. p65 and L1CAM were diffusely expressed, and a CDKN2A/B deletion was present. This is the first report of an extra‐central nervous system tumor with a ZFTA::RELA fusion. The tumor partly displayed an overlapping histology with that of chondroid lipoma, suggesting that it may represent a hitherto undescribed malignant chondroid lipoma with an alternative ZFTA fusion.

Novel ZFTA::NCOA1 fusion in chondroid lipoma

“…5 Interestingly, the recently described 'malignant chondroid lipoma' harboured a novel ZFTA::RELA gene fusion, a fusion reported in the majority of supratentorial ependymomas. 4 The presence of identical gene fusions in chondroid lipoma and ependymoma/ependymoma-like tumours with mesenchymal differentiation, pathological entities with distinct morphologies and clinical behaviour is intriguing, although shared genetic alterations have been previously reported in several unrelated tumours, including identical PHF1-rearrangements in ossifying fibromyxoid tumour and endometrial stroma sarcoma, EWSR1::NFATC2 in haemangioma, simple bone cyst and round cell sarcoma and ETV6::NTRK3 in infantile fibrosarcoma, leukaemia and secretory breast carcinoma, among others. 8,9 In summary, we report the first case, to our knowledge, of a chondroid lipoma harbouring an alternate ZFTA::NCOA1 gene fusion, expanding the genetic signatures of these rare tumours.…”

“…[1][2][3] To date, no alternate gene fusions have been reported in these tumours. Recently, Sumida et al 4 described a distinct liposarcoma with a fatal outcome with ZFTA::RELA gene rearrangement. In addition to frankly malignant areas, including cytological atypia, frequent mitotic activity, necrosis and vascular invasion, this unusual liposarcoma also showed areas indistinguishable from chondroid lipoma.…”