Abstract
Calcifying aponeurotic fibroma (CAF) is a rare benign but locally aggressive mesenchymal tumor that primarily occurs in the distal extremities of children and adolescents. It typically presents as a slow-growing, painless, poorly circumscribed mass, often of prolonged duration. Radiographs may reveal a soft-tissue mass with a variable extent of fine stippled calcifications. On magnetic resonance imaging, CAF usually appears as an ill-defined subcutaneous mass with low to intermediate signal intensity on T1-weighted sequences and heterogenous high signal intensity on T2-weighted sequences. Areas of calcification exhibit low signal intensity on all pulse sequences. Intense heterogeneous enhancement is seen after intravenous contrast administration. Histologically, CAF is characterized by a fibromatosis-like component and a nodular calcified component. By immunohistochemistry, the tumor cells are variably positive for smooth muscle actin, muscle-specific actin and CD99 but negative for desmin and β-catenin. Moreover, frequent expression of ETS transcription factor ERG (ERG) and epidermal growth factor (EGF) has been demonstrated. Recent molecular studies have identified the presence of a recurrent fibronectin 1 (FN1)-EGF gene fusion. Surgical excision is the treatment of choice for CAF, but local recurrence is common due to its infiltrative nature. This review provides an updated overview of the clinical, radiological, morphological, immunohistochemical and molecular genetic features of CAF and discusses the differential diagnosis of this uncommon condition.
- Calcifying aponeurotic fibroma
- calcified chondroid mesenchymal neoplasm
- lipofibromatosis
- fibronectin 1
- epidermal growth factor
- fusion gene
- review
Introduction
Calcifying aponeurotic fibroma (CAF), formerly known as juvenile aponeurotic fibroma, is a rare benign but locally aggressive mesenchymal tumor first described by Keasbey in 1953 (1). It belongs to the fibroblastic/myofibroblastic tumor group according to the latest World Health Organization (WHO) classification of soft tissue tumors (2). The etiology of this peculiar tumor is unknown.
CAF can show clinical, radiological and histological overlaps with a variety of benign and aggressive mesenchymal tumors such as inclusion body fibromatosis (IBF), lipofibromatosis (LPF), soft tissue chondroma (STC), calcified chondroid mesenchymal neoplasm (CCMN) and bizarre parosteal osteochondromatous proliferation (BPOP). The diagnosis of CAF can often be challenging on the basis of imaging alone. Advances in knowledge of the histological and molecular features of CAF are leading to more accurate diagnosis and appropriate management.
This review provides valuable insights into the clinical, radiological, histopathological and molecular genetic features of CAF. In addition, we will discuss the differential diagnosis of this unusual lesion.
Clinical Features
CAF occurs most commonly in children and adolescents with a peak incidence between the ages of 5 and 15 years (2). Several cases have been encountered in adults (3-5). There is a male predominance. CAF typically presents as a slow-growing, painless, poorly circumscribed, subcutaneous mass in the distal extremities, particularly the palm of the hand and the sole of the foot. It may also occur in less common sites such as the trunk and proximal extremities (6). The lesion has a predilection for the deep volar fascia, tendons and aponeuroses and is usually less than 3 cm in size (7). Complete surgical excision with preservation of function is the treatment of choice for CAF. Local recurrence occurs in up to 53% of cases (6, 7) and is usually seen within 3 years. The risk of local recurrence appears to be higher in children under 5 years of age (7). In general, simple re-excision of local recurrence rather than more aggressive resection is preferred to maintain function. Malignant transformation has been described in at least one case (8), but it is exceptionally rare.
Radiological Features
Radiographs usually reveal a non-specific soft-tissue mass with or without fine stippled calcifications. Although extrinsic pressure erosion/scalloping of the adjacent bone has been reported in a few cases (9-11), the underlying bone is typically normal. Ultrasonography (US) may show a well-defined or ill-defined, hypoechoic or mixed echoic mass with no significant vascularity (4, 11-13). Microlithiasis can be seen on US (13). Computed tomography (CT) is optimal for displaying the calcified areas of the lesion, with other regions showing non-specific soft-tissue attenuation (3, 14). Magnetic resonance imaging (MRI) exhibits an ill-defined subcutaneous mass with low to intermediate signal intensity on T1-weighted sequences and heterogenous high signal intensity on T2-weighted sequences (3, 13, 15, 16). The calcified areas typically show low signal intensity on all plus sequences. Contrast-enhanced MRI demonstrates intense heterogenous enhancement (3, 13, 15, 17).
Histological and Immunohistochemical Features
The definitive diagnosis of CAF is made based on histopathological examination. Grossly, CAF usually appears as a firm or rubbery, ill-defined mass with a gray-white, gritty cut surface. Histologically, CAF is characterized by a fibromatosis-like component and a nodular calcified component (2) (Figure 1). The fibromatosis-like areas are moderately cellular and consist of uniform, plump spindle cells without significant nuclear atypia (Figure 2A). The nodular calcified areas are less cellular and contain islands of calcification surrounded by more rounded, epithelioid cells (Figure 2B). Osteoclast-type giant cells are frequently present. Cartilaginous metaplasia may be seen in long-standing lesions (3). Mitotic figures are scare and necrosis is absent. Immunohistochemically, the tumor cells are variably positive for smooth muscle actin (SMA), muscle-specific actin (MSA) and CD99. In the chondroid areas, S100 is usually positive (6). More recently, frequent expression of ETS transcription factor ERG (ERG) and epidermal growth factor (EGF) has been demonstrated in CAF (12, 18). Immunostain for desmin and β-catenin is typically negative (6, 19).
Low-power view of calcifying aponeurotic fibroma highlighting the presence of a fibromatosis-like component and a nodular calcified component.
High-power view of calcifying aponeurotic fibroma. (A) The fibromatosis-like areas are composed of uniform, plump spindle cells without significant nuclear atypia. (B) The calcified areas contain epithelioid fibroblasts and scattered giant cells.
Pathogenesis
Only one case of CAF has been cytogenetically characterized in the literature, showing an ins(2;4) (q35;q25q?) (18). Most notably, a molecular study by Puls et al. (18) demonstrated the presence of a recurrent fibronectin 1 (FN1)-EGF gene fusion. The same fusion has also been detected in a subset of LPFs (20). FN1, located on chromosome 2q35, encodes fibronectin, a ubiquitous extracellular matrix protein, that is implicated in the regulation of cell adhesion, migration and proliferation (21). Interestingly, the presence of FN1 fusions with various gene partners have been reported in other mesenchymal neoplasms, including CCMN (22), STC (23), synovial chondromatosis (23) and phosphaturic mesenchymal tumor (24). EGF, located on chromosome 4q25, encodes prepro-EGF which can activate epidermal growth factor receptor (EGFR), a transmembrane receptor tyrosine kinase. EGF is widely expressed in the body and plays a fundamental role in development, tissue regeneration and ion transport (25). Moreover, EGF has been shown to upregulate FN1 expression in human dermal fibroblasts at the level of post-transcription (26). These findings suggest that the FN1-EGF fusion gene may possibly drive pathogenesis via an autocrine mechanism in CAF. Further functional studies are needed to fully understand the exact pathogenesis of CAF.
Differential Diagnosis
The differential diagnosis of CAF is broad and includes IBF, LPF, STC, CCMN and BPOP. The corresponding clinicopathological and molecular characteristics are summarized in Table I.
Major differential diagnosis of calcifying aponeurotic fibroma.
IBF, also known as infantile digital fibromatosis, is a rare benign myofibroblastic tumor that most commonly occurs in the fingers and toes of infants and young children (27). Although rare, synchronous or metachronous multifocality has been reported (28, 29). There is no significant sex predominance (27). IBF typically presents as a small (usually <2 cm), slow-growing, painless, dome-shaped cutaneous nodule. Interestingly, lesions may spontaneously regress (30-32). Current treatment options include function-preserving excision for symptomatic IBF and serial observation or intralesional steroid injection for asymptomatic IBF (33). Local recurrence occurs in 61-75% of cases (27). There is no documented risk of malignant transformation or distant metastasis. Radiographs may show soft-tissue edema (34). Unlike CAF, calcification is absent. Histologically, IBF is composed of a proliferation of bland spindle cells arranged in whorls, short fascicles or storiform patterns (27). Mitotic figures are rare. The most pathognomonic feature is the presence of round, eosinophilic, intracytoplasmic inclusions. Immunohistochemically, the tumor cells are positive for SMA, calponin, desmin and CD99 (29). Nuclear immunoreactivity for β-catenin is usually absent. To date, there is no reproducible cytogenetic or molecular alteration.
LPF is a rare intermediate (locally aggressive) mesenchymal tumor that most commonly occurs in the hands and feet of infants and young children (35). There is a male predominance (36). LPF typically presents as a slow-growing, painless, poorly demarcated subcutaneous mass. Complete surgical excision with preservation of adjacent neurovascular structures is the treatment of choice for LPF. Local recurrence occurs in 33-72% of cases (37, 38). There is no documented risk of malignant transformation or distant metastasis. Radiographs may show soft-tissue thickening with fat-type radiolucency (36). MRI usually reveals an ill-defined mass with variable proportions of adipocytic and solid components. The histological features of LPF overlap with CAF (37). However, unlike CAF, LPF lacks nodular foci with calcification and cartilage formation. Immunohistochemically, the tumor cells are positive for CD34 and CD99. Immunoreactivity for SMA is variable. A three-way translocation, t(4;9;6)(q21;q22;q2?4), has been described in one case (39). As mentioned above, the FN1-EGF gene fusion has been identified in four cases (20), suggesting a link to CAF. Al-Ibraheemi et al. (20) postulated that activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathway might be implicated in the pathogenesis of LPF.
STC is a relatively rare benign chondrogenic tumor that most commonly occurs in the hands and feet of middle-aged adults. There is a slight male predominance (40). STC typically presents as a small (usually <2 cm), solitary, slow-growing, painless mass. Complete surgical excision is the treatment of choice for STC. Local recurrence occurs in 15-20% of cases (40). There is no documented risk of malignant transformation or distant metastasis (41). Radiographs may show a soft-tissue mass with focal ringlike or curvilinear calcifications (42). STC does not involve the underlying bone. MRI usually reveals a well-demarcated, extraosseous mass with intermediate signal intensity on T1-weighted sequences and high signal intensity on T2-weighted sequences. Histologically, STC is composed of lobules of mature hyaline cartilage delineated by fibrous septa. Chondroblastoma-like variant is hypercellular and contains enlarged chondrocytes within a variable amount of chondroid matrix and osteoclast-type giant cells (43), recently reclassified as CCMN (22). Like CAF, expression of ERG and EGF seems to be common in STC (18, 44). Cytogenetic studies have shown several different aberrations, including rearrangements of 12q13-15 and trisomy 5 (45-50). In addition, a high mobility group AT-hook 2 (HMGA2)-LIM domain containing preferred translocation partner in lipoma (LPP) gene fusion has been identified in one case (50). Recently, FN1 gene rearrangements were detected in 50% of cases (23). Most notably, all cases with FN1 alterations exhibited grungy calcification, suggesting a diagnosis of the chondroblastoma-like variant. Fusions of FN1 to fibroblast growth factor receptor 1 (FGFR1) or fibroblast growth factor receptor 2 (FGFR2) have also been demonstrated in a subset of STCs with grungy matrix calcification (23).
CCMN is a recently recognized entity that predominantly occurs in the distal extremities and temporomandibular joint (TMJ) of adults, with hypercellular chondroid histology and frequent FN1 gene fusions (22). It encompasses chondroblastoma-like STC, chondroid tenosynovial giant cell tumor (TGCT) and tophaceous pseudogout (51). There is a slight female predominance (52). CCMN typically presents as a small (mean 2.1 cm), solitary, slow-growing, painless mass (52, 53). Complete surgical excision is the treatment of choice for CCMN. Local recurrence has been reported in only two cases after incomplete excision (53, 54). Although CCMN may be focally infiltrative (55), its prognosis is generally favorable. There is no documented risk of malignant transformation or distant metastasis (51). Radiographs generally show a nodular soft-tissue mass with internal calcifications (53). On MRI, the lesion usually reveals low to intermediate signal intensity on T1-weighted sequences and high signal intensity on T2-weighted sequences (53). Histologically, CCMN shows a multinodular growth pattern and is characterized by a proliferation of ovoid to stellae cells in an abundant chondroid or cartilaginous matrix, often with coarse, grungy, irregular or lace-like calcifications. Mitotic figures are very few and necrosis is absent. The immunophenotype is variable and non-specific. The most common molecular alteration in CCMN is FN1 gene rearrangement, involving various fusion partners such as FGFR1, FGFR2, fibroblast growth factor receptor 3 (FGFR3), MER proto-oncogene, tyrosine kinase (MERTK), neurotrophic receptor tyrosine kinase 1 (NTRK1), TEK receptor tyrosine kinase (TEK), proteoglycan 4 (PRG4), bone morphogenetic protein receptor type 2 (BMPR2) and ArfGAP with FG repeats 1 (AGFG1) (22, 52, 53, 55-57). In addition, 11 cases harbored platelet derived growth factor receptor alpha (PDGFRA)-ubiquitin specific peptidase 8 (USP8) fusions (54, 55, 57, 58), one case exhibited a FGFR1-PLAG1 zinc finger (PLAG1) fusion (22) and one case showed a collagen type I alpha 2 chain (COL1A2)-microRNA 29b-1 (MIR29B1) fusion (55). Interestingly, Benard et al. (55) reported that all cases harboring FN1-TEK fusions showed chondroid TGCT-like features and were located in the TMJ.
BPOP is a rare benign surface-based bone lesion that predominantly occurs in the hands and feet of young and early middle-aged adults (59). There is no significant sex predominance (60). BPOP typically presents as a firm, painless mass of variable duration. The lesion has a predilection for the small bones and is usually less than 3 cm in size (60). Complete surgical excision is the treatment of choice for symptomatic BPOP. Local recurrence occurs in 11-64% of cases (60). Malignant transformation has been reported in one case (61). Radiographs may show a well-defined, pedunculated or sessile mass arising from the cortical surface of bone. On MRI, the lesion usually reveals low to intermediate signal intensity on T1-weighted sequences and variable signal intensity on T2-weighted sequences (60). Histologically, BPOP is characterized by the presence of ‘blue bone’ and consists of a variable mixture of cartilage, bone and fibrous tissue (59). The immunophenotype is essentially non-specific. Unlike CAF, BPOP is cytogenetically characterized by a t(1;17) translocation or inv(7)(q21-22) (62-68). Moreover, rearrangements of collagen type I alpha 1 chain (COL1A1) or COL1A2 have been identified in a significant subset of cases (69). The COL1A2-long intergenic non-protein coding RNA, P53 induced transcript (LINC-PINT) and COL1A1-MIR29B2 and MIR29C host gene (MIR29B2CHG) fusions have been demonstrated in three cases and one case, respectively (69).
Conclusion
CAF is a rare benign mesenchymal tumor that predominantly occurs in the distal extremities of children and adolescents. Surgery is the mainstay of treatment for CAF, but local recurrence is common. CAF is histologically characterized by bland spindle cells and less cellular areas of calcification with epithelioid fibroblasts. Expression of ERG and EGF is frequently seen, although the immunophenotype is essentially non-specific. A recurrent FN1-EGF gene fusion is the hallmark of CAF. Further investigations are required to better delineate the relationship between CAF and CCMN.
Footnotes
Authors’ Contributions
JN researched the literature and drafted the article. YS and MK collected the data. KK and 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.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this article.
- Received September 16, 2025.
- Revision received October 1, 2025.
- Accepted October 20, 2025.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
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).
