Nodular Fasciitis
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Nodular Fasciitis is a benign, but rapidly progressive myofibroblastic proliferation that may exert mass effect on structures within the ocular adnexa. Further challenging its diagnosis, Nodular Fasciitis is a histopathologic mimic of soft tissue sarcomas. This article will summarize the defining clinical, histopathologic, molecular genetic, and radiographic features of Nodular Fasciitis. Awareness of this diagnosis is essential for appropriate patient counseling, avoidance of unnecessary alarm from misclassification as an aggressive sarcoma, or confusion with relatively indolent lesions such as dermoid cysts.
Disease Entity
Nodular fasciitis (NF) is a benign, rapidly growing myofibroblastic proliferation that most commonly arises in the upper extremities but can occur throughout the body, including the periorbital and ocular adnexal region.1 Although rare in this location, with fewer than 1% of NF cases occurring in the orbit, periorbital NF has been well documented since the first large ocular series established its characteristic presentation as a fast-growing, well-circumscribed mass that frequently mimics sarcomas on histology.1–4 Despite these worrisome clinical and histologic features, periorbital NF follows a uniformly benign course, typically resolving after simple excision with recurrence rates of only 1-2%. 5
Etiology
NF was previously described as a reactive process from chronic mechanical irritation that may be associated with preceding trauma and floppy eyelids.5,6 However, NF is established as true neoplasm with the discovery of recurrent USP6 gene fusions.1,2 Particularly, an unique gene fusion, MYH9-USP6, initially reported with up to 90% prevalence in NF. 7 Subsequent studies have demonstrated that USP6 FISH has a sensitivity of 86% and specificity of 100% for diagnosis of NF in morphologically definitive cases.8 Over 20 novel fusion partners of USP6 fusion partners have been identified including COL1A1, COL1A2, COL3A1, SPARC, TPM4, EIF5A, and others. 9
Risk Factors
NF is most commonly diagnosed in adults aged 20-40 years, with a peak incidence in the third decade.5 Only 10% of cases occur in the pediatric population, which is most commonly reported in the head and neck region.10 There are mixed reports of gender predilection that some literature reports male predominance while some series reports female predilection for females.11 Some case reports noted preceding trauma as mentioned previously; however, the etiology associated with trauma remains inconclusive. 5
General Pathology /Pathophysiology
Gross Pathology:
Lesions are solid, nodular, rubbery, or firm masses; biopsy specimens are typically pink-tan to yellow-tan, lobulated, and smooth. 5,12
Microscopically, NF is relatively well-circumscribed but unencapsulated nodular masses composed of cytologically bland, uniform spindle cells and stellate fibroblasts in a myxoid stroma with scattered mitoses, but no significant cytologic atypia and represents benign cytology. 1,13
Immunohistochemistry:
NF has been shown to express positivity of smooth muscle actin (SMA), vimentin and KP1 (histiocyte marker), while it stains negative for desmin, S100, SOX10, Keratin, Leu-7, Type IV Collagen, or Laminin.14–16 While case reports of NF in the trunk region have captured rare occurrences of estrogen receptor expression, subsequent cases of periorbital NF in pregnant women have not shown expression of estrogen receptors, making this theory inconclusive. 14,15,17
Molecular Genetics and USP6 Fusion Diversity:
The pathogenesis involves fusion of the entire coding region of USP6 (chromosome 17p13) under the transcriptional control of the partner gene promoter, leading to overexpression of USP6 through promoter-swapping.7 A recent comprehensive morphomolecular study of 175 USP6-associated neoplasms found that only 46.6% of NF cases resulted in the classic MYH9-USP6 fusion, with 53.4% showing non-MYH9 fusions. Notably, classic histological features of NF strongly correlated with MYH9-USP6 fusion, while specific locations such as intramuscular or intra-articular were significantly associated with non-MYH9 fusions.18 Over 20 novel partners of USP6 fusion partners have been identified including COL1A1, COL1A2, COL3A1, SPARC, TPM4, EIF5A, and others.9 One should be aware that break-apart FISH analysis can result in false negatives in some cases, and next-generation RNA sequencing may be required to identify USP6 fusions with non-MYH9 partners. In light of NF’s clinical and histologic presentation, which is difficult to distinguish from sarcomas, this genetic marker has arisen as a key diagnostic tool in numerous studies.
Diagnosis
History
Patients typically present with a rapidly growing mass that develops over days to weeks (median of 2 weeks). Duration of symptoms prior to presentation ranges from less than 1 week to several months (median 6 months for intraarticular lesions). Many do not have a known trigger, but some patients report preceding trauma or infection.
Physical Examination
NF is described as painless, firm, solid, nodular, rubbery, or firm masses. 1 The mass may be fixed to the surrounding fascia but typically mobile from overlying skin.19 Additionally, overlying skin may show erythema or retraction in some rare cases. 13 Ulceration of the epidermis may occur in intradermal variants.12
Clinical Diagnosis
Clinical diagnosis is challenging as nodular fasciitis mimics malignancy due to rapid growth and aggressive appearance. The diagnosis is rarely entertained preoperatively and requires pathological confirmation.
Diagnostic Procedures
Imaging:
Challenges associated with identifying NF from the differential for a palpable periorbital mass- which includes dermoid cyst, epidermal inclusion cyst, fibroma, and lipomas has drawn focus to the radiographic features.
CT: NF appears as a discrete mass ranging from 1-5cm, localization to the subcutaneous tissue, and solid or cystic nature.20 Cystic lesions have been observed with peripheral rim enhancement and nodular texture. 20,21
MRI: Solid lesions have been described with isointensity to muscle on T1 and T2 weighted imaging.20,22 The "fascial tail sign”, thickening of the adjacent fascial layer with notable enhancement, has been observed in both ultrasound and MRI studies.23–25 In one case series, the “fascial tail sign” was observed in 83.3% of cases in one series and is significantly more frequent in NF than other soft tissue lesions (P<0.001).26 Importantly, NF and myxofibrosarcoma (MFS) can share the "fascial tail sign", but several features that favor MFS are age greater than 46 years, tumor size greater than 4 cm, peritumoral edema, enhancement heterogeneity, and longer fascial tail.27 The "cloud sign", which refers to a cloudy or heterogenous intensity, appears only in NF and may further help differentiation.27 Additionally, the "inverted target sign" and "solar halo sign" occurs when the lesion has a T2 hyperintense center from the myxoid stroma with intense peripheral enhancement.25 The latter two radiographic signs have been reported to be slightly more common in NF than other soft tissue lesions.25
Ultrasound: NF has been shown to present as hypoechoic or anechoic cystic masses with minimal doppler signal.23,24 Some cases reported bony erosion, remodeling, and destructive changes. 21,22
Biopsy:
Fine-needle aspiration: benign-appearing spindle cells, collagen, and myxoid material
Core or excisional biopsy: Required for definitive diagnosis with histopathology and immunohistochemistry
The value of biopsy proven diagnosis remains significant given the extensive overlap in clinical and histologic presentation with sarcomas.28 Misdiagnosis as sarcoma, or missing the diagnosis of sarcoma, represent two detrimental mistakes that can be avoided by management with excision.
Molecular Testing:
USP6 FISH (break-apart probe): Sensitivity 86%, specificity 100%.8 The sensitivity of USP6 FISH is significantly impacted by lesion age. A lesion less than 1 month shows 80% USP6 break-apart signals and old lesions (greater than 3 months), shows as low as 14-27%.29
Next-generation sequencing (NGS): Can identify specific USP6 fusion partners and resolve ambiguous FISH cases. One case series reported a strong positive relationship (p = 0.000) between USP6 break-apart signals and mitotic counts and a strong negative correlation (p = 0.000) between percentage of USP6 break-apart signals and the lifetime.29
Investigations into molecular markers of NF have demonstrated that NF does not stain positively for desmin, S100, SOX10, Keratin, Leu-7, Type IV Collagen, or Laminin.14–16 Instead, NF has been shown to express SMA and vimentin. Case reports of NF in the trunk region have captured rare occurrences of estrogen receptor expression.17 However, subsequent cases of periorbital NF in pregnant women have not shown expression of estrogen receptors, making this theory inconclusive.
Laboratory Test
No specific laboratory tests are diagnostic. Diagnosis relies on histopathology, immunohistochemistry, and molecular testing.
Differential Diagnosis
Benign Lesions: proliferative fasciitis/myositis, myofibroma, desmoid-type fibromatosis, dermatofibroma, solitary fibrous tumor, and inflammatory fibrous histiocytoma.
Malignant Lesions:
Soft-tissue sarcomas (most important to exclude), myxofibrosarcoma, dermatofibrosarcoma, low-grade fibromyxoid sarcoma, rhabdomyosarcoma, low-grade fibromyxoid sarcoma.
Management
General Treatment
The management of nodular fasciitis has evolved to conservative observation or simple excision due to its self-limited nature and spontaneous regression.
Medical Therapy
Observation: Nonsurgical observation can lead to spontaneous complete resolution in 3-8 weeks (median 4 weeks) in appropriately selected cases diagnosed by fine-needle aspiration.30
Intralesional Corticosteroids: Some case reports have documented successful treatment using intralesional triamcinolone injections.28
Medical Follow-up
If patients are managed with observation, reassess in 3-8 weeks for spontaneous resolution. If the lesion is persistent, surgical excision should be.30
Surgery
Although nodular fasciitis can spontaneously regress, surgical excision remains the most common management approach as most cases are fast growing masses needing tissue biopsy to conform histologically or molecularly. Conservative local excision with preservation of normal anatomy and function has been the primary treatment and has been observed to be curative. Complete surgical excision achieves recurrence rates of only 1-2%.5 It is also important to avoid radical surgery as this is benign pathology.
Complications
Surgical Complications are rare and minor including residual firmness and tenderness at the surgical site 5
Prognosis
The prognosis for nodular fasciitis is excellent with low recurrences rate 5
Recurrence Rate: True nodular fasciitis is a nonrecurrent lesion. In a large series of 114 patients with 116 lesions, no recurrence was noted.31 Recurrence of a lesion originally diagnosed as nodular fasciitis should prompt careful reappraisal of the pathologic findings, as misdiagnosis is likely.
Metastasis and mortality: Metastasis and mortality are not expected from typical nodular fasciitis.12 Extremely rare reports of metastasis exist, but these likely represent misdiagnosed cases or a distinct entity termed "malignant nodular fasciitis" or "nodular fasciitis-like myofibroblastic sarcoma." 32
References
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2. Shields JA, Shields CL, Christian C, Eagle RC. Orbital nodular fasciitis simulating a dermoid cyst in an 8-month-old child. Case report and review of the literature. Ophthal Plast Reconstr Surg. 2001;17(2):144-148. doi:10.1097/00002341-200103000-00015
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4. Meffert JJ, Kennard CD, Davis TL, Quinn BD. Intradermal nodular fasciitis presenting as an eyelid mass. Int J Dermatol. 1996;35(8):548-552. doi:10.1111/j.1365-4362.1996.tb03652.x
5. Hseu A, Watters K, Perez-Atayde A, Silvera VM, Rahbar R. Pediatric nodular fasciitis in the head and neck: evaluation and management. JAMA Otolaryngol-- Head Neck Surg. 2015;141(1):54-59. doi:10.1001/jamaoto.2014.2797
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8. Shin C, Low I, Ng D, Oei P, Miles C, Symmans P. USP6 gene rearrangement in nodular fasciitis and histological mimics. Histopathology. 2016;69(5):784-791. doi:10.1111/his.13011
9. Balko J, Stanek M, Krskova L, Zamecnik J. Unusual fusion gene rearrangements in patients with nodular fasciitis: a study of rare and novel USP6 fusion partners with a review of the literature. J Clin Pathol. 2024;77(6):411-416. doi:10.1136/jcp-2023-208768
10. Stout AP. Pseudosarcomatous fascitis in children. Cancer. 1961;14:1216-1222. doi:10.1002/1097-0142(196111/12)14:6<1216::aid-cncr2820140611>3.0.co;2-w
11. Price EB, Silliphant WM, Shuman R. Nodular fasciitis: a clinicopathologic analysis of 65 cases. Am J Clin Pathol. 1961;35:122-136. doi:10.1093/ajcp/35.2.122
12. de Feraudy S, Fletcher CDM. Intradermal nodular fasciitis: a rare lesion analyzed in a series of 24 cases. Am J Surg Pathol. 2010;34(9):1377-1381. doi:10.1097/PAS.0b013e3181ed7374
13. Cloutier JM, Kunder CA, Charville GW, et al. Nodular fasciitis of the breast: clinicopathologic and molecular characterization with identification of novel USP6 fusion partners. Mod Pathol Off J U S Can Acad Pathol Inc. 2021;34(10):1865-1875. doi:10.1038/s41379-021-00844-4
14. Skippen B, Tomlinson J, Tumuluri K. Periorbital Nodular Fasciitis in Pregnancy: Case Report and Review of the Literature. Ophthal Plast Reconstr Surg. 2016;32(1):e1-3. doi:10.1097/IOP.0000000000000408
15. Phillips BN, Eiseman AS. Periorbital nodular fasciitis arising during pregnancy. Indian J Ophthalmol. 2014;62(4):520-521. doi:10.4103/0301-4738.99862
16. Anzeljc AJ, Oliveira AM, Grossniklaus HE, Kim HJ, Hayek B. Nodular Fasciitis of the Orbit: A Case Report Confirmed by Molecular Cytogenetic Analysis. Ophthal Plast Reconstr Surg. 2017;33(3S Suppl 1):S152-S155. doi:10.1097/IOP.0000000000000649
17. Kayaselçuk F, Demirhan B, Kayaselçuk U, Ozerdem OR, Tuncer I. Vimentin, smooth muscle actin, desmin, S-100 protein, p53, and estrogen receptor expression in elastofibroma and nodular fasciitis. Ann Diagn Pathol. 2002;6(2):94-99. doi:10.1053/adpa.2002.32377
18. Cordier F, Van Dorpe J, Sciot R, et al. A morphomolecular study of 175 “USP6-associated neoplasms”: The USP6 fusion partner strongly depends on morphology and location. Histopathology. 2026;88(4):898-910. doi:10.1111/his.70057
19. Yanagisawa A, Okada H. Nodular fasciitis with degeneration and regression. J Craniofac Surg. 2008;19(4):1167-1170. doi:10.1097/SCS.0b013e318176ac1a
20. Kim ST, Kim HJ, Park SW, Baek CH, Byun HS, Kim YM. Nodular fasciitis in the head and neck: CT and MR imaging findings. AJNR Am J Neuroradiol. 2005;26(10):2617-2623.
21. Tom Liu R, Henkelman E, Popescu O, Yin VT. Nodular fasciitis: A rapidly enlarging destructive periorbital mass in an infant. Am J Ophthalmol Case Rep. 2019;13:119-121. doi:10.1016/j.ajoc.2018.04.019
22. Compton CJ, Clark JD, Thompson MP, Lee HBH, Nunery WR. Nodular Fasciitis of the Orbit. Ophthal Plast Reconstr Surg. 2016;32(6):e154-e156. doi:10.1097/IOP.0000000000000346
23. Yen HH, Chiou HJ, Chou YH, Chen CH, Guo WY. Nodular Fasciitis: Sonographic-Pathologic Correlation. Ultrasound Med Biol. 2017;43(4):860-867. doi:10.1016/j.ultrasmedbio.2016.12.001
24. Boffano P, Campisi P, Forni P, Ramieri G, Berrone S. Nodular fasciitis in the maxillary region. J Craniofac Surg. 2012;23(6):e558-560. doi:10.1097/SCS.0b013e31825cef5d
25. Hu PA, Zhou ZR. Imaging findings of radiologically misdiagnosed nodular fasciitis. Acta Radiol. 2019;60(5):663-669. doi:10.1177/0284185118788894
26. Choi YJ, Lee IS, Song YS, Kim JI, Choi KU, Yi J. Clinical and Magnetic Resonance Imaging Findings for Differentiating Nodular Fasciitis and Myxofibrosarcoma: Correlation With “Fascial Tail” Sign. J Comput Assist Tomogr. 2025;49(6):958-965. doi:10.1097/RCT.0000000000001757
27. Wu SY, Zhao J, Chen HY, et al. MR imaging features and a redefinition of the classification system for nodular fasciitis. Medicine (Baltimore). 2020;99(45):e22906. doi:10.1097/MD.0000000000022906
28. Keren S, Hildebrand D, Wilson S, McCallum E, Norris JH. The management of periorbital nodular fasciitis using intra-lesional triamcinolone: a case report and review of the literature. Orbit. 2021;40(4):333-337. doi:10.1080/01676830.2020.1787465
29. Sápi Z, Lippai Z, Papp G, et al. Nodular fasciitis: a comprehensive, time-correlated investigation of 17 cases. Mod Pathol Off J U S Can Acad Pathol Inc. 2021;34(12):2192-2199. doi:10.1038/s41379-021-00883-x
30. Stanley MW, Skoog L, Tani EM, Horwitz CA. Nodular fasciitis: spontaneous resolution following diagnosis by fine-needle aspiration. Diagn Cytopathol. 1993;9(3):322-324. doi:10.1002/dc.2840090316
31. Bernstein KE, Lattes R. Nodular (pseudosarcomatous) fasciitis, a nonrecurrent lesion: clinicopathologic study of 134 cases. Cancer. 1982;49(8):1668-1678. doi:10.1002/1097-0142(19820415)49:8<1668::aid-cncr2820490823>3.0.co;2-9
32. Saoud C, Agaimy A, Stoehr R, et al. Nodular fasciitis: a case series unveiling novel and rare gene fusions, including two cases with aggressive clinical behavior. Virchows Arch Int J Pathol. 2025;486(6):1235-1245. doi:10.1007/s00428-025-04040-6
