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Review Article - (2025) Volume 16, Issue 1

Nodular fasciitis associated with atypical clinicopathological features: a review of the USP6 fusion gene partner
Kazumi Fujioka*
 
Department of Radiology, Nihon University School of Medicine, Tokyo, Japan
 
*Correspondence: Kazumi Fujioka, Department of Radiology, Nihon University School of Medicine, Tokyo, Japan, Email:

Received: 14-Jan-2025, Manuscript No. JCM-25-28305; Editor assigned: 16-Jan-2025, Pre QC No. JCM-25-28305; Reviewed: 30-Jan-2025, QC No. JCM-25-28305; Revised: 06-Feb-2025, Manuscript No. JCM-25-28305; Published: 14-Feb-2025, DOI: 10.35248/2157-2518.25.16.464

Abstract

USP6 gene rearrangement has been identified in the most of Nodular Fasciitis (NF) cases. Though the detection of several USP6 fusion partners has been identified, most of nodular fasciitis cases have exhibited the presence of MYH9- USP6 gene fusion. Recently, a literature review of rare intradermal nodular fasciitis focusing on the genetic analysis has been provided, suggesting that the detection of USP6 gene rearrangement may be the very useful and important genetic analysis for accurate diagnosis in even intradermal nodular fasciitis. The result provided MYH9, EIF5A and TPM4 as a fusion partner with USP6 in rare intradermal nodular fasciitis. In this review, the author summarized the rare nodular fasciitis accompanied by atypical clinicopathological findings including recurrence and/or metastasis, malignant morphology, atypical mitosis and different fusion partners with USP6. The result provided that USP6 rearrangement is a potential tool for accurate diagnosis in atypical nodular fasciitis. Several fusion partners including PPP6R3, MYH9, EIF5A, CALD1, COL6A2, PAFAH1B1 and SREBF1 with USP6 have been identified by Fluorescence In Situ Hybridization (FISH) and/or Next Generation Sequencing (NGS), suggesting that these fusion genes may have different biological spectrum reflecting unusual clinicopathological features. Further study is needed to clarify the biological spectrum of USP6 fusion partner to avoid aggressive and invasive treatment for nodular fasciitis associated with atypical clinicopathological features. Meanwhile, a few cases of nodular fasciitis with atypical manifestations and typical MYH9- USP6 fusion have been revealed, therefore it is significant to identify USP6 rearrangement for diagnostic conformation of nodular fasciitis by molecular analysis.

Keywords

Nodular fasciitis; USP6-associated neoplasia; Biological spectrum; USP6 fusion gene partner; Atypical clinicopathological features

Introduction

USP6 gene rearrangement has been identified in the most of NF. Although the detection of numerous USP6 fusion partners has been identified, nodular fasciitis cases have typically exhibited the presence of MYH9-USP6 fusion gene. The novel and rare fusion patterns with USP6 including KIF1A, TPM4, SPARC, EIF5A, MIR22HG and COL1A2 have been also reported [1]. Recently, rare intradermal nodular fasciitis focusing on the molecular analysis has been reviewed [2]. In this article, the author summarized the nodular fasciitis associated with atypical clinicopathological feature including recurrence and/or metastasis, malignant morphology, atypical mitosis and several USP6 fusion gene partners having different biological spectrum.

Transient neoplastic nature in nodular fasciitis

NF is a benign soft tissue tumor of fibroblastic/myofibroblastic differentiation that was first described in 1955 by Konwaler et al. and a rare intradermal nodular fasciitis has been firstly reported in 1990 [3,4]. Erickson-Johnson et al. suggested that USP6 transcriptional upregulation may be the driving force behind the high proliferative activity and growth and the consistent involutional nature of NF [5]. Previous study emphasized that presentation of clinical, ultrasonographic and pathological features features of NF are attributed to the cytogenetic nature having high proliferative growth and involutional nature [6,7]. Regarding clinical manifestations, NF presents most typically in the upper extremities, the trunk and the head and neck in the ages between 20 years and 40 years. The subcutaneous, fascial, intramuscular and rarely intradermal type have been reported with a peculiar clinical manifestation characterized by rapid, self-limited growth and spontaneous regression after a few weeks [8,9]. Pathologically. NF typically featured uniform spindled cells arranged in irregularity intersecting short fascicles and occasional storiform patterns. NF contains of myofibroblasts with brisk mitotic activity without atypical mitosis [10]. Immunohistochemical findings showed that spindle cells of NF were positive for Smooth Muscle Actin (SMA) [1].

Literature Review

A novel fusion partners with USP6 in nodular fasciitis

Genetic analysis of USP6 gene rearrangements has been identified in the most of NF cases. The detection of the USP6 gene rearrangement has also been recognized as a diagnostic procedure in cases with morphological uncertainty [1,11]. While MYH9 gene has been identified as the most common USP6 partner. Wang et al. described that MYH9-USP6 gene fusion has been observed in most of NF cases [12]. The detection of other USP6 fusion partners includes TPM4, EIF5A, PPP6R3, CTNNB, SPARC, THBS2, COL6A2, TNC, SEC31A, COL1A1, COL1A2, COL3A1, CALU, NACA, SLFN11, LDHA, SERP1NH1, PDLIM7, MYL12A, PAFAH1B1 and MIR22HG as previously reported [1,13,14]. The previous study showed the new and rare fusion patterns with USP6 in NF including one novel KIF1A and five rare types (TPM4, SPARC, EIF5A, MIR22HG, COL1A2). A novel partner, KIF1A gene has been identified in patient with superficial lesion of the arm [1]. Meanwhile, palmar nodular fasciitis with atypical morphology and a novel SREBF1-USP6 fusion gene has been demonstrated [15]. The diagnosis of lowgrade fibroblastic/myofibroblatic tumors at acral locations is important due to the differential diagnosis from malignant tumors. Recently, the current knowledge and trends of the intradermal nodular fasciitis focusing on the molecular analysis have been outlined, exhibiting USP6 rearrangement in all cases and two cases of MYH9, one case of EIF5A and one case of TPM4 as a fusion partner with USP6. The detection of USP6 gene rearrangement using FISH may be the very useful and important genetic analysis for accurate diagnosis in even intradermal NF as previously described [2]. The identification of numerous fusion partners with USP6 in NF has been common, furthermore the detection of USP6 fusion partner may contribute to understand the biological nature resulting in accurate diagnosis and the prevention for the unnecessary aggressive therapy [1]. The feature of USP6 fusion partner may reflect biological nature, therefore the identification supports the daily pathological practice, particularly in cases with malignant potential findings.

USP6-Associated Neoplasms (UAN)

USP6 gene rearrangements have been demonstrated in Aneurysmal Bone Cyst (ABC), NF, Myositis Ossificans (MO), Fibro-Osseous Pseudotumor of digits (FP) and Fibroma of Tendon Sheath (FTS) such as cellular type [10]. Due to the sharing a common pathogenesis with so-called USP6 rearrangement, these diseases are referred to as USP6-Associated Neoplasms (UAN) representing clinicopathological similarities. Recent study has also suggested that these diseases share similar clinicopathological features [14]. The transcriptional upregulation of USP6 is made through a promotor-swapping mechanism leading to the USP6 overexpression. The USP6 overexpression promotes tumorigenesis through several pathways including Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-kB), Wingless-Related Integration Site (Wnt/β-catenin), Janus kinase-signal transducer and activator of transcription (JAK-STAT3) and c-jun and transforms mesenchymal cells [14,16]. Multimodality imaging findings along with molecular analysis of USP6-associated neoplasms have been reported [17]. Regarding FTS, it is clinically important to differentiate between FTS and Giant Cell Tumor of the Tendon Sheath (GCTTS). Previous report provided that GCTTS showed hypoechoic nodule with vascularity on US study and represented low signal intensity on T1 and T2 weighted MR images due to the hemosiderin [18]. While molecular analysis is helpful for accurate diagnosis in FTS. USP6 rearrangements were previously revealed in cellular cases of FTS and found also in hypocellular and hypercellular FTSs [18-20]. FISH and targeted nextgeneration Ribo Nucleic Acid (RNA) sequencing can be a useful tool to detect a USP6 rearrangement. However, FISH is limited due to decalcified materials, hypocellular lesions or old age. Meanwhile NGS has limitations for decalcification and poor DNA quality of the lesion and/or the gene rearrangement with a new unknown fusion partner [10].

Nodular fasciitis with atypical clinicopathological features and different USP6 fusion partner

The author previously outlined NF as USP6-associated neoplasia along with therapeutic strategy [21]. In addition to the presentations of clinical, ulrtrasonographic and pathological appearances of NF, the evaluation of percentage of USP6 breakapart FISH signals reflecting lifetime and mitotic counts in NF may be a potential procedure for accurate diagnosis [7,21,22]. It is known that USP6 promotes tumorigenesis through multiple pathways including Wnt, Jak-1, c-Jun and STAT3 [14,23-25]. Previous report has emphasized that the detection of USP6 gene rearrangement may be the very useful and important molecular finding for even intradermal nodular fasciitis [2]. A fusion partner with USP6 showed that MYH9, EIF5A and TPM4 genes have been identified in rare intradermal nodular fasciitis [2]. In this review, the author summarized the rare NF with atypical clinicopathological findings and molecular features at (Tables 1 and 2). Until now, only nine cases have been reported [15, 26-33]. PPP6R3-USP6 fusion has been shown in two cases of NF accompanied with malignant manifestation [26, 27]. Guo et al. showed a case of NF at the subcutaneous region of the thigh, 6.2 cm in size with multiple recurrences and metastatic manifestation showing classic histologic findings, the amplification and unbalanced rearrangement in FISH and novel PPP6R3-USP6 gene fusion by molecular analysis [26]. Another case represented the mass at the muscle of upper arm, 13.2 cm in size with aggressive and no regression growth with local invasion exhibiting typical histologic feature, amplification and unbalanced rearrangement in FISH pattern and PPP6R3- USP6 gene fusion by targeted RNA sequencing [27]. Two cases accompanied with malignant morphology in NF have been demonstrated [29-30]. Papke et al. reported a morphologically malignant NF with striking nuclear pleomorphism, exhibiting a USP6 translocation in FISH and the novel CALD1-USP6 fusion by next-generation-sequencing [29]. Another case represented NF with malignant morphology showing pronounced pleomorphism, atypical mitoses features and a myoid immunophenotype and USP6 rearrangement with a collagen type VI, alpha 2 (COL6A2)-USP6 fusion was confirmed by FISH, Archer Fusion Plex (Sarcoma Panel) and RNA sequencing [30]. Cases of the atypical mitoses in pathologic features have been documented [31,32]. Lenz et al. showed one atypical mitoses in pathology harboring a novel EIF5A-USP6 fusion gene by NGS [32]. Though clinicopathological findings are benign, the unbalanced rearrangement and unusual break point of USP6 with a novel PAFAH1B1-USP6 fusion have been show n , leading to the diagnosis of NF with uncertain malignant potential [31]. This case revealed the occurrence of USP6 breakpoint in intron 8. According to the previous report, PAFAH1B1-USP6 fusion has been demonstrated in two cases of ABC only [31]. Meanwhile, two cases of palmer NF have been reported suggesting that this entity exhibited aggressive presentation as previously described [15,28]. An aggressive behavior of NF protruding from the palm with ulnar nerve palsy has been previously reported demonstrating that the diagnosis of NF is supported by the identification of the MYH9-USP6 fusion gene [28]. Recently, palmar nodular fasciitis with a novel SREBF1-USP6 fusion gene has been recognized, suggesting that it is important to differentiate between this entity and low-grade fibroblastic/myofibroblastic tumors such as sarcoma [15]. In particular, as palmer NF tends to show aggressive manifestation, therefore the confirmation of USP6 rearrangement may be a potential procedure for accurate diagnosis of NF. While, in addition to the previous study of NF with atypical presentation and common MYH9-USP6 fusion, recent study also provided a large intramuscular NF with pathologically local infiltrative margin diagnosed by USP6 rearrangement in FISH [28,33]. It is important to differentiate between intramuscular NF and Low- Grade Myofibroblastic Sarcoma (LGMFS) for pathologically moderate cellular atypia and diffusely infiltrative margin [33]. Additionally, the recurrence of the skin NF with common MYH9-USP6 fusion has been shown [1]. As a few cases of NF with common MYH9-USP6 gene fusion accompanied by atypical manifestation have been reported, furthermore, the detection of USP6 rearrangement is a potential tool for making accurate diagnosis of NF [1,28,33]. Because the identification of the USP6 gene rearrangement has been demonstrated as a significant diagnostic tool in cases accompanied by morphological uncertainty [1,11]. In this review, the results showed that eight cases revealed USP6 rearrangement, exhibiting PPP6R3, MYH9, EIF5A, CALD1, COL6A2, PAFAH1B1 and SREBF1 as a fusion partner with USP6 by FISH and/or NGS. The detection of USP6 rearrangement is a potential tool for accurate diagnosis in NF associated with atypical clinicopathological presentations including recurrence and/or metastases, malignant morphology, atypical mitosis and different USP6 fusion partner. Several USP6 fusion partners have been identified, suggesting that these fusion genes may have different biological spectrum reflecting atypical clinicopathological behavior. Though NF associated with typical MYH9-USP6 fusion gene and atypical clinicopathological features have been shown, thereby, it is significant to identify USP6 rearrangement for diagnostic confirmation of NF.

Study Age/gender Location/depth Atypical clinicopathological features
Guo et al. [26 ] 42/f Thigh/subcutaneous Recurrence and metastases
Teramura et al. [27] 27/m Upper arm/muscle Malignant transformation
Sawamura et al. [28] 53/f Palm/NA Aggressive behavior
Lenz et al. [32] 41/f Forearm/predominantly dermis Atypical mitosis
Papke et al. [29] 7/m Upper extremity/NA Malignant morphology
Tomassen et al. [30] 10/m Chest wall/muscle Malignant morphology
Qiu et al. [31] 22-Month/m Scapular/subcutaneous Atypical mitosis
Wang et al. [33] 27/m Upper arm/muscle Malignant morphology
Mejbel et al. [15] 60/m Palm/NA Atypical morphology

Table 1: Clinicopathological features in atypical nodular fasciitis.

Study Age/gender FISH NGS USP6 fusion partner
Guo et al. [26 ] 42/f USP6rearrangement NA PPP6R3
Teramura et al. [27] 27/m USP6rearrangement Done PPP6R3
Sawamura et al. [28] 53/f USP6rearrangement NA MYH9
Lenz et al. [32] 41/f USP6rearrangement Done EIF5A
Papke et al. [29] 7/m USP6 rearrangement Done CALD1
Tomassen et al. [30] 10/m USP6rearrangement Done COL6A2
Qiu et al. [31] 22-Month/m USP6rearrangement Done PAFAH1B1
Wang et al. [33] 27/m USP6rearrangement NA MYH9
Mejbel et al. [15] 60/m NA Done SREBF1

Table 2: USP6 fusion gene partner in atypical nodular fasciitis.

Regarding the therapeutic strategy, the inhibition of the USP6- related genes including Jak-1, Frizzled genes and c-Jun may be potential treatment for recurrent and inoperable ABC [21,23-25].

Though the process of NF is typically rapid growth, selflimited, and spontaneous regression. It is putative that the inhibition of USP6-related genes might be the potential therapeutic strategies for the extremely rare malignant behavior of recurrence and metastasis in nodular fasciitis shown by USP6- PPP6R3 gene fusion as previously mentioned [21].

Discussion

Though the detection of several USP6 fusion partners has been identified, most of NF cases have exhibited the presence of MYH9-USP6 gene fusion. The novel and rare fusion patterns with USP6 including new KIF1A and rare TPM4, SPARC, EIF5A, MIR22HG and COL1A2 have been reported [1]. Recently, a literature review of rare intradermal nodular fasciitis with emphasis on the molecular analysis has been provided, suggesting that the detection of USP6 gene rearrangement may be the very useful and important genetic analysis for accurate diagnosis in even intradermal NF [2]. The result showed MYH9, EIF5A and TPM4 as a fusion partner with USP6 in rare intradermal NF [2]. In this article, the author outlined the atypical NF with clinicopathological manifestations including recurrence and/or metastasis, malignant morphology, atypical mitosis and several USP6 fusion gene partners having different biological spectrum. USP6 rearrangement is a potential tool for accurate diagnosis in even unusual NF. Several fusion partners with USP6 including PPP6R3, MYH9, EIF5A, CALD1, COL6A2, PAFAH1B1 and SREBF1 have been identified by FISH and/or NGS, suggesting these fusion genes may have different biological spectrum reflecting atypical clinicopathological behavior. Because NF with unusual fusion partners with USP6 tends to show malignant clinicopathological manifestations, further study is needed to clarify the biological spectrum of fusion partner of USP6 to avoid the overtreatment for atypical NF. Meanwhile, it is important to differentiate between palmer NF and low-grade fibroblastic/myofibroblastic tumors such as sarcoma in the palmar lesions [15]. As palmer NF tends to show locally aggressive and indistinguishable from sarcoma, therefore the confirmation of USP6 rearrangement may be a potential procedure for accurate diagnosis of NF [28]. Though NF is generally benign and self-limited soft tissue tumor, a few cases with atypical manifestations and the presence of MYH9-USP6 fusion gene have been reported, therefore it is very important to confirm USP6 rearrangement for accurate diagnosis of NF by FISH and NGS. Further studies are also needed to verify for the biology in NF associated with atypical clinicopathological presentation and typical MYH9-USP6 fusion [29-33].

Conclusion

A few cases of nodular fasciitis associated with unusual behavior and typical MYH9-USP6 fusion have been documented, therefore it is important to identify USP6 rearrangement for diagnostic conformation of nodular fasciitis by molecular analysis. The detection of USP6 rearrangement is a potential tool for accurate diagnosis in atypical nodular fasciitis associated with clinicopatho logical presentation including recurrence and metastases, malignant morphology, atypical mitosis and different USP6 fusion partner. Several USP6 fusion partners including PPP6R3, MYH9, EIF5A, CALD1 , COL6A2, PAFAH1B1 and SREBF1 have been identified by FISH and/or NGS in atypical nodular fasciitis, suggesting that these fusion genes may have different biological spectrum reflecting unusual clinicopathological behavior. Further study is needed to verify the biological spectrum of USP6 fusion partner for atypical nodular fasciitis.

Conflict of Interest

Author declares that no conflicts of interest.

Funding

None

References

Citation: Fujioka K (2025). Nodular Fasciitis Associated with Atypical Clinicopathological Features: A Review of the USP6 Fusion Gene Partner. J Carcinog Mutagen. 16:464

Copyright: © 2025 Fujioka K. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.