Novel EIF5A-USP6 Gene Fusion in Nodular Fasciitis Associated With Unusual Pathologic Features: A Report of a Case and Review of the Literature

Abstract

Nodular fasciitis (NF) is a benign self-limiting soft tissue lesion that has long been considered a reactive process. Recently, however, the USP6 gene rearrangement has been discovered, and the neoplastic nature of this tumor was suggested. Since then, many fusion partners of the USP6 gene have been reported, with the MYH9 gene as the most common. In this article, we describe a case of NF with a novel EIF5A-USP6 gene fusion associated with unusual pathological features. A 41-year-old healthy woman with a painful, rapidly growing subcutaneous mass on the left forearm with a size of 0.8 cm is presented. A soft tissue fragment measuring 1 cm was surgically excised. Owing to positive surgical margins, re-excision was performed, yielding another 2-cm fragment. The lesion was extensively histologically investigated. Immunohistochemical and molecular–genetic analysis, namely fluorescence in situ hybridization, next-generation sequencing, and reverse transcriptase-polymerase chain reaction, were also performed. Histology revealed a dermally located, mitotically active myofibroblastic proliferation with myxoid areas that ulcerated the overlying epidermis. One atypical mitotic figure was also found. The lesion showed positive immunohistochemical staining with smooth muscle actin, whereas S100 protein and CD34 stains were negative. Using fluorescence in situ hybridization, the USP6 gene rearrangement was detected and subsequent analysis using the Archer fusionPlex Sarcoma kit revealed a novel EIF5A-USP6 gene fusion. In the appropriate clinicopathological context, the detection of USP6 gene rearrangement is extremely useful when diagnosing NF, significantly reducing the risk of misdiagnosis and inappropriate overtreatment.

USP6-Associated Neoplasms: A Rapidly Expanding Family of Lesions

“…38 Since then, a growing number of novel fusion partners are detected in NF, including RRBP1, CALU, CTNNB1, MIR22HG, SPARC, THBS2, COL6A2, 39 SERPINH1 and COL3A1, 40 and EIF5A. 41 Remarkably, in 2016, a case of NF in a 42-year-old woman demonstrating malignant, metastatic behavior with a PPP6R3-USP6 fusion and amplification was described. 42 This case showed a protracted clinical course with multiple recurrences and finally metastatic behavior over a period of 10 years.…”

Fusion of the Lumican (LUM) Gene With the Ubiquitin Specific Peptidase 6 (USP6) Gene in an Aneurysmal Bone Cyst Carrying a t(12;17)(q21;p13) Chromosome Translocation

“…Apart from aneurysmal bone cyst, USP6 activation by promoter-swapping gene fusion has also been found in nodular fasciitis, cranial fasciitis, and myositis ossificans (38)(39)(40)(41)(42)(43)(44)(45). Furthermore, USP6 rearrangements were detected in a subset of cellular fibromas of tendon sheath which share similar histological features with nodular fasciitis (46).…”

Nodular fasciitis: USP6-associated neoplasia through multiple pathways

“…The author previously has reported a common subcutaneous NF [4] and a rare intradermal type [5]. Though this entity of the intradermal type have very rarely occurred, De Feraudy et al [6] have studied intradermal nodular fasciitis as a rare lesion analyzed in a series of 24 cases, and recently the lesion involved both the dermis and subcutis as a superficial nodular fasciitis [7] and a dermally located lesion [8] have been reported in the dermatologic field. NF presents most typically in the upper extremities, the trunk, and the head and neck.…”

“…SEC31A, EIF5A, COL1A1, COL1A2, PAFAH1B1, SERP1NH1, COL3A1 have been also identified [38][39][40][41][42][43][44][45]. Regarding EIF5A, the USP6 gene rearrangement was shown by using FISH and a subsequent analysis demonstrated a novel EIF5A-USP6 gene fusion by means of the Archer fusionPlex Sarcoma kit [8]. They mentioned that the genesis of NF is also caused by Wnt signaling pathway which is the essential target of USP6 [8].…”

“…Regarding EIF5A, the USP6 gene rearrangement was shown by using FISH and a subsequent analysis demonstrated a novel EIF5A-USP6 gene fusion by means of the Archer fusionPlex Sarcoma kit [8]. They mentioned that the genesis of NF is also caused by Wnt signaling pathway which is the essential target of USP6 [8]. PPP6R3-USP6 fusion has been shown in two cases of NF accompanied with malignant manifestation [44,45].Regarding the cutaneous NF, Kumar et al [30] have described the presence of the USP6 rearrangement and MYH9-USP6 fusion, suggesting that the similar cytogenetic nature has been revealed both in subcutaneous NF and intradermal type.…”