While virtually all cases of NF and variants have had excellent prognoses, the two cases of individuals with an USP6-PPP6R3 fusion gene in their NF tumor cells had less favorable prognoses: their tumors were locally invasive, repeatedly relapsed after surgical removal, and grew progressively larger over 2 and 10 years of observations. Treatment
Some cases of NF have regressed after being partially biopsied suggesting that a watchful waiting approach may be appropriate after biopsy in some cases of these tumors. In all events, the most common and generally accepted first-line treatment for most cases of NF, craniofacial fasciitis, and intravascular fasciitis tumors is surgical removal. In almost all cases this removal is curative, i.e. tumor recurrences are uncommon, even in cases where the tumor is only partially removed. Furthermore, tumor recurrences are typically cured by simple re-excisions. NF cases have also been successfully treated with corticosteroid drugs (e.g. triamcinolone) injected directly into the tumor; this treatment has been most often used for patients with recurrent tumors. Some studies, however, have suggested reevaluating the diagnosis in recurrent NF tumors to ensure the diagnosis is correct. Surgical and corticosteroid interventions may need to be performed promptly in order to avoid expansion of a cranial tumor into the skulls interior or an intravascular fasciitis tumor from compromising blood flood flow. Prognosis
Two cases of NF in which their tumor cells expressed a USP6-PPP6R3 fusion gene had highly aggressive, locally invasive, repeatedly recurrent (after surgical removal), and progressively enlarging tumors over 2 and ten years. One case developed multiple metastases (i.e.
ribosome binding protein 1) gene, CALU (calumenin) gene, CTNNB1 (catenin beta 1) gene, MIR22HG (produces the MIR22HG long non-coding RNA) gene, SPARC (secreted protein acidic and cysteine rich [also termed osteonectin]) gene, THBS2 (thrombospondin-2) gene, COL6A2 (collagen type VI alpha 2 chain) gene, SEC31A {SEC31 homolog A, COPII coat complex component) gene, EIF5A (eukaryotic translation initiation factor 5A) gene, COL1A1 (collagen type I alpha 1 chain) gene, COL1A2 (collagen type I alpha 2 chain) gene, COL3A1 (collagen type III alpha 1 chain) gene, PAFAH1B1 (platelet activating factor acetylhydrolase 1b regulatory subunit 1) gene, SERPINH1 (serpin family H member 1) gene which produces heat shock protein 47, PDLIM7 (PDZ and LIM domain protein 7) gene, and MYL12A (myosin regulatory light chain 12A) gene. While very few cases have been analyzed to date, USP6-containing fusion genes have been found in the tumor cells of 7 of 15 tested cases of cranial fasciitis and six of  six tested cases of intravascular fasciitis.All of the USP6-containing fusion genes in NF and variants overproduce a chimeric protein containing a part of the USP6 genes product, ubiquitin carboxyl-terminal hydrolase 6a, that has uncontrolled deubiquitinating enzyme activity. This may result in the inappropriate stimulation of  multiple cell signaling pathways including the Wnt signaling pathway, one of the JAK-STAT signaling pathways (i.e. the Jak1-STAT3 pathway), the c-Jun signaling pathway, and the NF-κB signaling pathway. Each of these pathways, when inappropriately activated, has been implicated in promoting the development of various tumors and cancers.