Giant Nodular Fasciitis Originating From The Humeral Periosteum: A Diagnostic Challenge

Background: Nodular fasciitis (NF) is a self-limiting, benign, broblastic, and myobroblastic tumor that mostly occurs in the subcutaneous supercial fascia, although there are reports of NF occurrences at atypical sites, such as intraneural and intra-articular locations. However, NF originating from the appendicular periosteum is extremely rare, and NF lesions usually are smaller than 4 cm. A large NF lesion of periosteal origin can be misdiagnosed as a malignant bone tumor and may cause overtreatment. Case presentation: This case report presents a large NF that originated from the humeral periosteum in an adult and was initially diagnosed intraoperatively as low-grade sarcoma, but later diagnosed as NF after post-resection histopathological evaluation. Furthermore, uorescence in situ hybridization analysis revealed a USP6 gene rearrangement that in NF[8]. Subsequently in 2013, Amary et al. found USP6 gene rearrangements in 91% of the 34 NF cases in their study, thereby making USP6 uorescein in situ hybridization (FISH) analysis a a reliable and useful ancillary diagnostic test for NF[9]. This report presents ndings from the rst case of large-sized NF originating from the humeral periosteum. We emphasize the importance of highlighting thisrare clinical entity, which usually represents a diagnosticdilemma.


Background
Nodular fasciitis (NF) was rst described as a pseudosarcomatous fasciitis by Konwaler et al. in 1955[1]. Similar to other soft-tissue sarcomas, NF is a rapidly growing, benign proliferation of broblasts and myo broblasts displaying abundant, spindle-shaped cellsand high mitotic activity [2].NF presents most typically in the upper extremities (46%), trunk (20%), and head and neck (18%) [3].The peak incidences of NF are seen at ages 20 and 40, often presenting with tenderness, and it is a rare disease in children [4].Most NF lesions are small, measuring less than 2 cm in diameter [3,4]. Periosteal fasciitis is considered a rare subtype ofNF, with some case reports in the published literature and most of those were published over 20 years ago; only one case of periosteal fasciitis has been published recently, in 2017. The frequently reported sites of periosteal fasciitis are the maxilla and the hand; however, there are no reports of periosteal fasciitis in the limbs, and all reported cases described tumors that were smaller than 5 cm.
As NF has a nonspeci c immunohistochemicalpro le [5][6][7], its histomorphological characteristics are the primary diagnostic criteria. Therefore, it remains a challenge to distinguish NF from other spindle cell lesions, particularly those of the myo broblastic lineage.
In 2011, Erickson-Johnson et al. reported the rearrangement of the ubiquitin-speci c protease 6 (USP6) gene on chromosome 17p13 as a recurrent and speci c nding in NF [8]. Subsequently in 2013, Amary et al. found USP6 gene rearrangements in 91% of the 34 NF cases in their study, thereby making USP6 uorescein in situ hybridization (FISH) analysis a a reliable and useful ancillary diagnostic test for NF [9].
This report presents ndings from the rst case of large-sized NF originating from the humeral periosteum. We emphasize the importance of highlighting thisrare clinical entity, which usually represents a diagnosticdilemma.

Case Presentation
A right axillary mass was incidentally found in a 46-year-old man approximately 1 month before he was hospitalized. An MRI scan showed high signal intensity of the agglomerated pressure-fat phase near the right axillary region. The MRI images showed a lesion measuring 62 × 58 × 44 mm 3 , with relatively well-demarcated margins. The lesion encircled the humerus, with localized thinning of the humeral cortex, and was closely related to the radial artery. The differential diagnosis of sarcoma was made, and the patient underwent surgical tumor resection. Intraoperatively, we identi ed a mass with an approximate diameter of 7 cm that was closely related to the humerus, with a relatively clear boundary that separated it from the surrounding tissue. The tumor was completely separated from the periosteum. The surgical specimen was intraoperatively subjected to rapid histopathological examination. Gross examination revealed a gray nodule measuring 7.5 × 4 × 4 cm 3 that had a reddish gray surface appearance on cross section and relatively tough texture (Fig. 1). Microscopically, the lesion mainly comprised spindle-shaped broblast-like cells,with mucinous degeneration, mild atypia of some cells, and 3-4 mitotic gures per 10 HPF. The intraoperative provisional pathological diagnosis was that the mass was a mesenchymal neoplasm; the nal diagnosis would be de nitively based on the postoperative pathology. The postoperative histopathology of the lesions revealedspindle-shaped tumor cells with abundant extracellular mucoid matrix( Fig. 2B and 2F); similarly, on examination of the frozen sections, some areas showed brous hyperplasia and hyaline degeneration (Fig. 1A), whereas other areas had extravasation of red blood cells (Fig. 2D). Tumor cells in areas with relatively high cellularity showed mild atypia( Fig. 2C and 2D) and mitotic gures (Fig. 2C). Immunohistochemistry showed that the specimen stained negative for CD34,S100, andβ-catenin; positive for CD10 and SMA (Fig. 3). FISH analysisrevealed aUSP6 gene fracture rearrangement ( Fig. 4) with signal patterns as follows: 1G1R1F 16.5%,1G1R 8.5%,2F 35.5%,1F 25.0%,1G1F 7.0%, and 1R1F 7.5%. was approximately 5 cm. Most of the cases were diagnosed by histomorphological features, and FISH was undertaken in only one case in the recent literature and showedUSP6 gene-related heterotopia. All patients were followed up, and there are no reports of recurrence (Table 1). In our case, NF was initially diagnosed by histomorphology and immunohistochemistry; however, because of the unusually large tumor and its periosteal origin, we undertook aUSP6 FISH examination. The results showed USP6-related ectopia, which further con rmed a diagnosis of NF. The patient has shown no recurrence on follow-up for 10 months. This report presents a rare case of clinical NF of the humeral periosteum with a tumor diameter of 7.5 cm. Due to its fast and in ltrative growth pattern, NFremains one of the most commonly misdiagnosed benign spindle cell neoplasms [5]. A common differential diagnosis of NF is low-grade malignant myo broblastic tumors because, despite their large size, the tumor cells are characterized by mild atypia;positive staining foractin, desmin,calponin,and CD34 (focal),and negative staining for S100 and nuclear β-catenin [12][13][14]. However, FISH shows no USP6 generelated ectopia, and myo broblastic tumors have a high recurrence after surgical resection.
Sometimes, it may be di cult to distinguish low-grade myxo brosarcoma from NF, especially in cases with small tumor volume and without speci c immunohistochemical markers. Nonetheless, curvilinear thin-walled blood vessels andpseudolipoblasts suggest the possibility of a myxo brosarcoma, and FISH examination shows no USP6 gene-related ectopia.
Low-grade malignant bromyxoid sarcoma is another differential diagnosis of NF. The identi cation can be comprehensively evaluated by immunohistochemical staining and molecular detection. Immunohistochemistry shows EMA positivity from focally to 80%, and MUC4 positivity has high sensitivity and speci city for the detection of bromyxoidsarcoma [15].Molecular genetics showFUS-CREB3L2 or FUS-CREB3L1 gene fusion (Table 2). Diffusely in ltrative growth, spindle cells arranged in a storiform pattern or fascicles Positive: actin, desmin, calponin, CD34(focal); negative: S100, nuclear β-catenin [12][13][14] Only one showed a circular chromosome Positive: SMA, negative: desmin and histiocytespeci c markers [28] No speci c aberration Immunohistochemical staining has no speci c signi cance in the identi cation of NF; however, it can be used as an auxiliary and differential diagnostic tool because spindle cells in NF often diffusely express SMA, and are negative for desmin [6]. Recent studies have shown that USP6 in situ hybridization has higher speci city and sensitivity in the diagnosis of NF [9], particularly in cases with uncharacteristic morphology.
Furthermore, NF can be accurately diagnosed by combining tumor morphological characteristics,immunohistochemical ndings, and USP6 detection, thereby avoiding misdiagnosis and overtreatment of patients.
NF poses a diagnostic challenge as it is often mistaken for a sarcoma, or easily misdiagnosed as a sarcomatous lesion such as malignant brous histiocytoma or brosarcoma, because of its rapid growth, rich cellularity, and poorly circumscribed nature. NF should be considered in a rapidly growing nodule with a relatively clear border in the upper limb, despite an atypical site and large tumor volume, because arelatively conservative diagnosis, especially during the surgery, could reduce overtreatment. Postoperative histopathological examination of whole sectionscan be combined with immunohistochemical staining and, if necessary, the diagnosis can be con rmed by molecular detection.

Consent for publication
Written informed consent was obtained from all patients involved in this review.

Availability of data and materials
The datasets used and/or analyzed during the current study are availablefrom the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests. Authors' contributions P.L.S. designed the review. S.L.Y. collected the data and prepared thedraft. J.L. , M.J. participated in data interpretation.P.L.S. and H.W.G. provided research fund. All authors read and approved the nal manuscript.