Abstract
Fibroma of tendon sheath (FTS) is a benign fibroblastic/myofibroblastic neoplasm that primarily occurs in the fingers and hands of young and middle-aged adults. The lesion typically presents as a small, firm, slow-growing, painless nodule. Ultrasonography usually shows a focal nodular mass with homogeneous hypoechogenicity. Magnetic resonance imaging reveals a well-defined nodular mass with decreased signal on all pulse sequences. No or minimal peripheral enhancement is often seen after intravenous contrast. Histologically, the lesion is well circumscribed and consists of bland spindle cells in a dense collagenous stroma with slit-like thin-walled vessels at the periphery. A cellular variant of FTS has also been described and shows at least a focal morphological overlap with nodular fasciitis. Immunohistochemistry does not play a significant role in the diagnosis of FTS. Cytogenetic studies have demonstrated the presence of 11q rearrangements. A significant subset of cellular variants of FTS are characterized by ubiquitin specific peptidase 6 (USP6) rearrangements, with a variety of fusion partners. Complete surgical excision is the treatment of choice. This review provides an updated overview of the clinical, radiological, histological, cytogenetic and molecular genetic features of FTS and discusses the differential diagnosis of this uncommon entity.
- Fibroma of tendon sheath
- desmoplastic fibroblastoma
- tenosynovial giant cell tumor
- nodular fasciitis
- USP6
- review
Introduction
Fibroma of tendon sheath (FTS) is a rare benign soft-tissue tumor first described in detail by Geschickter and Copeland (1) in 1949. Chung and Enzinger (2) subsequently described the largest series of 138 cases that became the basis of our understanding of this disease. According to the latest World Health Organization (WHO) classification of soft tissue and bone tumors (3), FTS belongs to the fibroblastic/myofibroblastic tumor group. FTS can show clinical and morphological overlaps with a variety of benign soft-tissue tumors, including desmoplastic fibroblastoma (DF), localized tenosynovial giant cell tumor (TSGCT) and nodular fasciitis (NF). The etiology of this tumor is unknown. Advances in knowledge of the imaging, histopathology and genomics of FTS are leading to more accurate diagnosis and appropriate treatment. In this article, we review the clinical, radiological, histological, cytogenetic and molecular genetic features of FTS. In addition, we will discuss the differential diagnosis of this entity.
Clinical Features
FTS has a peak incidence in the third to fifth decades of life, with a male predominance (2). It typically presents as a firm, slow-growing, painless nodule in the distal extremities, particularly the fingers and hands. Although rare, intra-articular involvement has been described (4-6). Tenderness or mild pain is seen in 31% of cases (2). The diameter ranges from 0.5 to 5.5 cm (median of 1.8 cm) (2). Simple excision is the treatment of choice. Local recurrence occurs in up to 24% of cases (2, 3), usually between 1 and 4 months following surgery. In our extensive experience, local recurrence is not aggressive and typically cured by simple re-excision. There is no documented risk for distant metastasis.
Radiological Features
Radiographs are usually unremarkable or may reveal a non-specific soft-tissue mass without calcification. Unlike localized TSGCT, extrinsic erosion/scalloping of the adjacent bone is extremely unusual (2). Ultrasonography will typically show a homogeneous hypoechoic nodule that is attached to the tendon sheath (7, 8). Blood flow patterns are variable on color Doppler imaging (7). On magnetic resonance imaging (MRI), the lesion is well-defined and adjacent to the tendon sheath. FTS typically exhibits low to intermediate signal intensity on both T1-weighted (Figure 1A) and T2-weighted (Figure 1B) images. Occasionally, the lesion reveals high signal intensity centrally with slightly low signal peripherally on T2-weighted images (9). Fox et al. (9) suggested that the signal characteristics might vary depending on the degree of cellularity and myxoid change. Contrast-enhanced MRI often demonstrates no or minimal peripheral enhancement (4, 8, 9). Recently, Emori et al. (10) reported that the signal intensity ratio calculated for the tumor and flexor tendon on T2-weighted images was helpful for distinguishing FTS from localized TSGCT. In that study, the T2 signal intensity ratio was significantly higher in localized TSGCT than in FTS.
Axial magnetic resonance images of fibroma of tendon sheath involving the hand. The mass (white arrowheads) shows low to intermediate signal intensity on both T1-weighted (A) and T2-weighted (B) sequences.
Histopathology
Grossly, FTS appears as a well-circumscribed, sometimes lobulated mass with a pearly-white or gray-white cut surface. Focal myxoid or cystic change may be present. Histologically, the lesion is well circumscribed and consists of bland spindle cells in a dense collagenous stroma. The characteristic histological finding of FTS is the presence of slit-like thin-walled vessels or clefts (Figure 2). Cytological atypia and necrosis are absent. A cellular variant of this tumor has also been described (2), closely resembling NF. Cellular FTS is generally defined as a tumor having areas of increased cellularity and an NF-like appearance as well as identifiable histological features of classical FTS. Immunohistochemically, the tumor cells are focally positive for smooth muscle actin (SMA) and HAM56 (11). Immunostains for CD34, S-100 protein, cytokeratin, β-catenin and FOS like 1 (FOSL1) are typically negative (12-14).
Histological features of fibroma of tendon sheath. The tumor is composed of bland spindle cells in a dense collagenous stroma. Slit-like vessels can be seen (hematoxylin and eosin staining, original magnification ×100).
Cytogenetic and Molecular Genetic Features
Clonal chromosomal aberrations have been detected in four cases of classical FTS (4, 15-17). Classical FTS displays mostly simple karyotypes characterized by one or few chromosomal rearrangements. These cytogenetic studies suggest that 11q rearrangements may be characteristic of classical FTS. It is of interest that rearrangements of 11q, in particular 11q12-13, are also seen in DF (18), which shares similar morphological features with classical FTS.
In 2016, Carter et al. (19) reported that ubiquitin specific protease 6 (USP6) (located on 17p13.2) rearrangements were found in 67% (6/9) of cellular FTS but not in classical FTS. Subsequently, Wang et al. (20) also reported that USP6 rearrangements were detected in 88% (7/8) of cellular FTS but not in classical FTS. Moreover, anchored multiplex polymerase chain reaction (PCR)/next generation sequencing (NGS) demonstrated the presence of USP6 fusions in 64% (7/11) of cellular FTS (21). On the other hand, Pižem et al. (22) reported that USP6 fusions were found in 94% (17/18) of FTS and classical FTS also showed the presence of USP6 fusions. The authors concluded that FTS, regardless of cellularity, can be defined by USP6 rearrangements/fusions. To date, various fusion partners of USP6 have been identified in FTS, including myosin heavy chain 9 (MYH9), collagen type I alpha 1 chain (COL1A1), pyruvate kinase M1/2 (PKM), regulator of chromosome condensation 1 (RCC1), asporin, (ASPN), collagen type III alpha 1 chain (COL3A1), MIR22 host gene (MIR22HG), catenin beta 1 (CTNNB1), secreted protein acidic and cysteine rich (SPARC), cyclase associated actin cytoskeleton regulatory protein 1 (CAP1), epithelial membrane protein 1 (EMP1), cytoskeleton regulator RNA (CYTOR), nuclear receptor subfamily 1 group D member 1 (NR1D1), RAB1A, member RAS oncogene family (RAB1A) and tenascin C (TNC) (20-23). Some fusion partners appear to be shared across neoplasms (24, 25). Further studies with a large number of cases are required to better understand the correlation between certain gene fusions and clinicopathological features.
Differential Diagnosis
The major differential diagnosis of FTS includes DF, localized TSGCT and NF. Recent advances in molecular genetics have contributed greatly to our understanding of these benign tumors. The corresponding clinicopathological and molecular characteristics are summarized in Table I.
Differential diagnosis of fibroma of tendon sheath.
DF, also known as collagenous fibroma, is a benign fibroblastic/myofibroblastic tumor that primarily arises in the subcutaneous tissue of upper extremities and limb girdles. It has a peak incidence in the fifth to seventh decades of life, with a male predominance (18). DF typically presents as a firm, slow-growing, painless mass. The diameter ranges from 1.0 to 20.0 cm (median of 3.0 cm) (26). On MRI, the lesion reveals prominent low signal intensity on all pulse sequences. Contrast-enhanced MRI demonstrates mild peripheral and septal enhancement (18). In our experience, it is often difficult to distinguish between DF and FTS by imaging alone. Simple excision is the treatment of choice. Unlike FTS, local recurrence has not been reported (18). Grossly, DF appears as a well-circumscribed mass with a white to gray-gray cut surface. Histologically, DF is hypocellular and consists of bland spindle to stellate-shaped cells in a dense collagenous stroma, closely resembling classical FTS. Most importantly, unlike FTS, DF shows diffuse, strong FOSL1 nuclear immunoreactivity (13). To date, clonal chromosomal aberrations have been identified in 11 cases of DF (27-33). These cytogenetic studies strongly suggest that DF is characterized by 11q12-13 rearrangements. Moreover, recent molecular studies demonstrate that FOSL1 rearrangements are recurrent genetic events in DF (34). The discovery of FOSL1 rearrangements has led to more precise diagnostics of DF.
Localized TSGCT, formerly known as giant cell tumor of tendon sheath, is a benign fibrohistiocytic tumor that typically presents as a firm, slow-growing, painless nodule or mass. It has a peak incidence in the third to fifth decades of life, with a female predominance (35). Like FTS, localized TSGCT predominantly occurs in the fingers and hands, in close proximity to the synovium of the tendon sheath. The diameter ranges from 0.5 to 4.0 cm (36). Although extrinsic erosion/scalloping of the adjacent bone is the most radiographic osseous finding associated with localized TSGCT, intraosseous invasion has also been described, suggesting an aggressive neoplasm (37-39). On MRI, the well-circumscribed lesion exhibits low to intermediate signal intensity on T1-weighted sequences, variable signal intensity on T2-weighted sequences and relatively high signal intensity on fluid-sensitive sequences. Contrast-enhanced MRI typically demonstrates intense and heterogeneous enhancement (40). Localized TSGCT can be managed by complete marginal excision. Local recurrence occurs in 4-30% of cases (36). Distant metastasis has been reported but is extremely rare (41, 42). Grossly, localized TSGCT appears as a well-circumscribed mass with a variably yellow, tan or whitish cut surface. Histologically, localized TSGCT consists of a mixture of mononuclear cells, osteoclast-like multinucleated giant cells, foamy macrophages and inflammatory cells. There are two types of mononuclear cells: small histiocyte-like cells and larger epithelioid cells (36). Diffuse and strong clusterin expression is seen in the large mononuclear cells (43). In addition, desmin is positive in 50% of cases and highlights large mononuclear cells (44). The cytogenetic hallmark of TSGCT is the presence of 1p13 rearrangements (39, 45, 46). The most frequent translocation is t(1;2)(p13;q37), leading to a collagen type VI alpha 3 chain (COL6A3)-colony stimulating factor 1 (CSF1) gene fusion. In recent years, there has been a remarkable breakthrough in the molecular profile of TSGCT. CSF1 rearrangements are present in 2-16% of tumor cells (47) and can be detected by fluorescence in situ hybridization (FISH) (48). TSGCT is caused by upregulation of the CSF1 gene, leading to aberrant CSF1 expression and recruitment of CSF1 receptor (CSF1R)-dependent macrophages. In selected cases, the finding of CSF1 rearrangements by FISH can support the diagnosis.
NF is a benign self-limited fibroblastic/myofibroblastic neoplasm that usually arises in the subcutaneous tissue and underlying fascia of upper extremities. It has a peak incidence in the third and fourth decades of life, with no definite sex predominance (49). Unlike FTS, NF usually presents as a rapidly growing, sometimes painful mass. NF usually measures less than 2 cm at patient presentation (49). On MRI, the lesion reveals low to intermediate signal intensity on T1-weighted sequences and intermediate to high signal intensity on T2-weighted sequences. Linear extension along the fascia (facial tail sign) would be helpful to suggest the diagnosis and mild surrounding edema can be seen (50). Contrast-enhanced MRI exhibits diffuse or peripheral enhancement (51). Spontaneous resolution is well documented, and simple excision is sufficient (24). Local recurrence is exceedingly rare and cured by simple re-excision. Distant metastasis and malignant transformation have been reported but are extremely uncommon (52, 53). Grossly, NF may appear as an unencapsulated, circumscribed or infiltrative mass with a variably grayish, tan or whitish cut surface (49). Histologically, NF consists of plump spindle-shaped cells in a collagenous or myxoid stroma. Mitotic activity is easily identified but atypical mitoses are not found. Extravasated erythrocytes, lymphocytes and osteoclast-like giant cells are frequently observed (49). Immunohistochemically, the neoplastic cells are positive for SMA. Focal desmin expression is occasionally found. To date, clonal chromosomal aberrations have been detected in five cases of NF (54-58). These cytogenetic studies indicate that rearrangements involving 3q21 and 15q22-26 are recurrent in NF. In 2011, Erickson-Johnson et al. (59) reported that USP6 rearrangements were found in 92% (44/48) of NF. In that study, MYH9 was identified as a novel fusion partner. Since then, various USP6 fusion partners have been detected in NF (24, 25, 60, 61). These molecular studies indicate that MYH9 is the most common fusion partner for USP6 in NF. Remarkably, it may be possible that amplifications of protein phosphatase 6 regulatory subunit 3 (PPP6R3)-USP6 fusion gene act as a driver of malignant transformation and progression in NF (52, 53).
Conclusion
FTS is a distinctive benign fibroblastic/myofibroblastic tumor with a low but non-negligible risk for local recurrence and no metastatic risk. MRI reveals a well-defined nodular mass with decreased signal on all pulse sequences which demonstrates no or minimal peripheral enhancement. Surgery is the mainstay of treatment for FTS, and local recurrence can usually be managed with re-excision. The characteristic histological finding of FTS is the presence of slit-like thin-walled vessels or clefts. Notably, it should be kept in mind that the histological features of the cellular type are identical to those of NF. 11q rearrangements are prominent in classical FTS, whereas a subset of FTSs, in particular the cellular type, are characterized by USP6 rearrangements. Further investigations are required to better delineate the relationship between cellular FTS and NF.
Footnotes
Authors’ Contributions
YS researched the literature and was a major contributor to writing the article. JN drafted the article. SN and MK collected the data. MA performed the histological evaluation. TK reviewed the article. All Authors read and approved the final article.
Conflicts of Interest
The Authors declare no conflicts of interest associated with this article.
Funding
No funding was received for conducting this study.
- Received December 9, 2024.
- Revision received December 18, 2024.
- Accepted December 19, 2024.
- Copyright © 2025, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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