Further studies are needed to determine which, if any, of these pathways are overactive in and can be successfully targeted with specific drug therapies to treat NF and its variants.Two cases of NF have tumor cells in which the USP6 gene has fuses with the  PPP6R3 (i.e. protein phosphatase 6 regulatory subunit 3) gene. In both of these cases, the tumors clearly showed malignant behavior. Diagnosis
NF may resemble and therefore be misdiagnosed as dermatofibrosarcoma protuberans, fibrosarcoma, malignant fibrous histiocytoma, spindle-cell melanoma (a rare form of melanoma,) leiomyosarcoma, and inflammatory myofibroblastic tumor. The diagnosis of NF and its variants depends on a combination of findings no single one of which is definitive. These findings are: the tumors: presentation (particularly its location in the cranium, within blood vessels, or outside of these areas); histopathology (particularly analyses of tumor cell mitoses which if atypical strongly suggest the tumor is not NF); presence of myofibroblasts that typically express muscle-specific actin, SMA, and vimentin and may express CD68 but generally do not express S100, desmin, trypsin, factor VIII, F4/80, or CD34 (lack of Cd34-expressing cells indicates that the tumor is not a sarcoma); and presence of typical neoplastic cells expressing an USP6-containing fusion gene. (USP6-containing fusion genes also occur in the tumor cells of aneurysmal bone cysts, fibroma of tendon sheaths, giant cell reparative granuloma, and myositis ossificans/fibro-osseous pseudotumor of digits.)
Gene abnormalities
Until recently, nodular fasciitis was considered a reaction to trauma or some other unidentified insult at the site where the tumor subsequently developed. However, recent findings indicate that up to 92% of NF tumors involve the self-limiting growth of a clone (i.e. a group of identical cells that share a common ancestry} of neoplastic cells that contain a fusion gene. Fusion genes are abnormal genes consisting of parts from two different genes that form as a result of large scale gene mutations such as chromosomal translocations, interstitial deletions, or inversions. The fusion gene found in NF tumor cells consists of a part of the USP6 gene combined with any one of numerous other genes. Its most common partner gene in NF is the MYH9 (i.e. myosin-9) gene. This USP6-MYH9 fusion gene forms as a result of a translocation of part of the USP6 gene located at band 13.2 on the long (or "q") arm of chromosome 17 with part of the MYH9 gene at band 13.2 on the short (or "p") arm of chromosome 22. Other genes that partner with the USP6 gene to form a fusion gene found in NF include the: RRBP1 (i.e.