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.

Biomedical Center Charles University Faculty of Medicine in Pilsen Pilsen Czech Republic

Bioptical Laboratory Ltd Pilsen Czech Republic

Cytohisto s r o Breclav Czech Republic

Department of Anatomy Histology and Embryology Faculty of Veterinary Medicine University of Veterinary and Pharmaceutical Sciences Brno Brno Czech Republic

Department of Orthopaedics Breclav Hospital Breclav Czech Republic; and

Department of Pathology Charles University Faculty of Medicine in Pilsen Pilsen Czech Republic

Department of Pathology Znojmo Hospital Znojmo Czech Republic

Department of Surgery Znojmo Hospital Znojmo Czech Republic

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Lazar A, Evans HL, Oliveira AM. Nodular fasciitis. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, et al, eds. WHO Classifcation of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2013:46–47.

de Feraudy S, Fletcher CD. Intradermal nodular fasciitis: a rare lesion analyzed in a series of 24 cases. Am J Surg Pathol. 2010;34:1377–1381.

Price EB Jr, Silliphant WM, Shuman R. Nodular fasciitis: a clinicopathologic analysis of 65 cases. Am J Clin Pathol. 1961;35:122–136.

Shimizu S, Hashimoto H, Enjoji M. Nodular fasciitis: an analysis of 250 patients. Patology. 1984;16:161–166.

Arbiser ZK, Folpe AL, Weiss SW. Consultative (expert) second opinions in soft tissue pathology. Analysis of problem-prone diagnostic situations. Am J Clin Pathol. 2001;116:473–476.

Erickson-Johnson MR, Chou MM, Evers BR, et al. Nodular fasciitis: a novelmodel of transient neoplasia induced by MYH9-USP6 gene fusion. Lab Incest. 2011;91:1427–1433.

Oliveira AM, Chou MM. The TRE17/USP6 oncogene: a riddle wrapped in a mystery inside an enigma. Front Biosci (Schol Ed). 2012;4:321–334.

Amary MF, Ye H, Berisha F, et al. Detection of USP6 gene rearrangement in nodular fasciitis: an important diagnostic tool. Virchows Arch. 2013;463:97–98.

Miettinen M. Fibroblast biology, fasciitis, retroperitoneal fibrosis, and keloids. In: Miettinen M, ed. Modern Soft Tissue Pathology: Tumors and Non-neoplastic Conditions. New York, NY: Cambridge University Press; 2010:181–206.

Skalova A, Vanecek T, Martinek P, et al. Molecular profiling of mammary analogue secretory carcinoma revealed a subset of tumors harboring a novel ETV6-RET translocation: report of 10 cases. Am J Surg Pathol. 2017;42:234–246.

Švajdler M, Michal M, Martínek P, et al. Fibro-osseous Pseudotumor of digits and myositis Ossificans show consistent COL1A1-USP6 rearrangement: a clinicopathological and genetic study of 27 cases. Hum Pathol. 2019;88:39–47.

Nakamura T, Hillova J, Mariage-Samson R, et al. A novel transcriptional unit of the tre oncogene widely expressed in human cancer cells. Oncogene. 1992;7:733–741.

Oliveira AM, Hsi BL, Weremowicz S, et al. USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst. Cancer Res. 2004;64:1920–1923.

Oliveira AM, Perez-Atayde AR, Inwards CY, et al. USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in socalled secondary aneurysmal bone cysts. Am J Pathol. 2004;165:1773–1780.

Oliveira AM, Perez-Atayde AR, Dal Cin P, et al. Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes. Oncogene. 2005;24:3419–3426.

Patel NR, Chrisinger JSA, Demicco EG, et al. USP6 activation in nodular fasciitis by promoter swapping gene fusions. Mod Pathol. 2017;30:1577–1588.

Erber R, Agaimy A. Misses and near misses in diagnosing nodular fasciitis and morphologically related reactive myofibroblastic proliferations: experience of a referral center with emphasis on frequency of USP6 gene rearrangements. Virchows Arch. 2018;473:351–360.

Oliveira AM, Chou MM. USP6-induced neoplasms: the biologic spectrum of aneurysmal bone cyst and nodular fasciitis. Hum Pathol. 2014;45:1–11.

Guo R, Wang X, Chou MM, et al. PPP6R3-USP6 amplification: novel oncogenic mechanism in malignant nodular fasciitis. Genes Chromosomes Cancer. 2016;55:640–649.

Lam SW, Cleton-Jansen AM, Cleven AHG, et al. Molecular analysis of gene fusions in bone and soft tissue tumors by anchored multiplex PCR-based targeted next-generation sequencing. J Mol Dian. 2018;20:653–663.

Bekers EM, Eijkelenboom A, Grünberg K, et al. Myositis ossificans—another condition with USP6 rearrangement, providing evidence of a relationship with nodular fasciitis and aneurysmal bone cyst. Ann Diagn Pathol. 2018;34:56–59.

Madan B, Walker MP, Young R, et al. USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds. Proc Natl Acad Sci U S A. 2016;113:E2945–E2954.

Jacquot C, Szymanska J, Nemana LJ, et al. Soft-tissue aneurysmal bone cyst with translocation t(17;17)(p13;q21) corresponding to COL1A1 and USP6 loci. Skeletal Radiol. 2015;44:1695–1699.

Agaram NP, LeLoarer FV, Zhang L, et al. USP6 gene rearrangements occur preferentially in giant cell reparative granulomas of the hands and feet but not in gnathic location. Hum Pathol. 2014;45:1147–1152.

Carter JM, Wang X, Dong J, et al. USP6 genetic rearrangements in cellular fibroma of tendon sheath. Mod Pathol. 2016;29:865–869.

Flucke U, Shepard SJ, Bekers EM, et al. Fibro-osseous pseudotumor of digits Expanding the spectrum of clonal transient neoplasms harboring USP6 rearrangement. Ann Diagn Pathol. 2018;35:53–55.

Shin C, Low I, Ng D, et al. USP6 gene rearrangement in nodular fasciitis and histological mimics. Histopathology. 2016;69:784–791.

Clement PM, Johansson HE, Wolff EC, et al. Differential expression of eIF5A-1 and eIF5A-2 in human cancer cells. FEBS J. 2006;273:1102–1114.

Nodular fasciitis: a case series unveiling novel and rare gene fusions, including two cases with aggressive clinical behavior

Unusual fusion gene rearrangements in patients with nodular fasciitis: a study of rare and novel USP6 fusion partners with a review of the literature