Benign infiltrative myofibroblastic neoplasms of childhood with USP6 gene rearrangement.

ABSTRACT

AIMS: Several morphologically overlapping (myo)fibroblastic neoplasms harbour USP6 fusions, including aneurysmal bone cysts, nodular fasciitis, myositis ossificans, cranial fasciitis, fibro-osseous pseudotumour of the digits, and cellular fibroma of the tendon sheath. USP6-induced neoplasms are almost universally benign and cured by local excision. We aim to highlight the diagnostic value of USP6 fusion detection in a series of aggressive-appearing paediatric myofibroblastic tumours. METHODS AND RESULTS: Three deep-seated, radiographically aggressive, and rapidly growing childhood myofibroblastic neoplasms were morphologically and molecularly characterised by USP6 break-apart fluorescence in-situ hybridisation (FISH), transcriptome sequencing, and targeted capture analysis. Each tumour occurred in the lower-extremity deep soft tissue of a child presenting with pain, limping, or a mass. In all three patients, imaging studies showed a solid mass that infiltrated into surrounding skeletal muscle or involved/eroded underlying bone. The biopsied tumours consisted of variably cellular myofibroblastic proliferations with variable mitotic activity that lacked overt malignant cytological features. FISH showed that all tumours had USP6 rearrangements. On the basis of these results, all three patients were treated with conservative excision with positive margins. The excised tumours had foci resembling nodular fasciitis, fibromatosis, and pseudosarcomatous proliferation. Next-generation sequencing revealed COL1A1-USP6 fusions in two tumours and a COL3A1-USP6 fusion in the third tumour. One tumour had a subclonal somatic APC in-frame deletion. No recurrence was observed during follow-up (8-40 months). CONCLUSION: We present a series of benign, but aggressive-appearing, USP6-rearranged myofibroblastic tumours. These deep-seated tumours had concerning clinical and radiographic presentations and did not fit into one distinct histological category. These cases highlight the diagnostic value of USP6 fusion detection to identify benign nondescript tumours of this group, especially those with aggressive features, to avoid overtreatment.