Infantile Digital Fibromatosis/Inclusion Body Fibromatosis: A Comprehensive Literature Review

Abstract

Infantile digital fibromatosis (IDF), or inclusion body fibromatosis, is a rare benign tumor that commonly presents as a solitary nodule composed of spindle cells within the dermis on the digits of infants and children. Evaluation often includes a biopsy and typical therapies include observation, intralesional corticosteroid injections, and complete surgical resection. Given the rarity of IDF, few clinicians have direct or extensive experience diagnosing or treating it. Here we present a comprehensive review of the presentation, diagnosis, and treatment for IDF.

Introduction

Infantile digital fibromatosis (IDF) is a rare tumor with as few as 200 reported cases [1]. IDF usually presents as a solitary nodule [2] in the dermis and is histopathologically composed of spindle cells, typically on the fingers and toes of children [1, 3]. The condition was originally described by Reye [3] in 1965 after he published a case series of spindle cell tumors sharing similar anatomic location, patient demographics, and histopathologic features. IDF is also known as inclusion body fibromatosis [4] because of the classic histopathologic finding of cytoplasmic inclusion bodies [3]. Additional names for IDF also include infantile digital myofibroblastoma and Reye tumor [5]. Multiple names for IDF, along with the existence of other fibromatoses unique to children, such as infantile myofibromatosis, juvenile aponeurotic fibroma, and juvenile hyaline fibromatosis, may result in confusion for clinicians [6]. Additionally, because of the rarity of IDF [1], few clinicians have experience diagnosing and treating this condition, and it has the potential to go undiagnosed or be suboptimally managed.

Clinical Presentation

IDF is a slow-growing tumor presenting as a nodule on the digits of infants and children [3]. Classically, the lateral and dorsal aspects of the last 4 digits are most commonly affected, while the hallux and thumb are typically spared [1, 2]. Nondigital involvement has been previously reported [7], though this is rare. IDF has not been reported to be associated with any genetic syndrome or systemic disease [8], though clinically similar lesions − lacking the characteristic inclusion bodies identifiable on histopathology − are associated with terminal osseous dysplasia with pigmentary defects, an X-linked dominant disorder [9].

In Reye's original description of IDF as an entity [3], it was noted that affected patients usually develop the tumor in the first year of life and that there is a similar incidence in males and females. In his report, many IDFs were also shown to recur following surgical excision [3]. A recent case series of 57 pediatric patients with IDF highlighted additional features for its clinical presentation, finding that 53 of the 57 patients had solitary lesions, while the remaining patients had two nodules [2]. Often, if there are two nodules, they may present as “kissing lesions” in which the tumors face one another on adjacent digits [10].

In the aforementioned case series, IDF was most commonly found on the second toe (n = 15), third finger (n = 15), and fourth finger (n = 12) [2]. Clinically, as shown in Figure 1, these nodules are described as painless, smooth surfaced, pink-red, dome-shaped [2], and less than 2 cm in size [11]. Similar to Reye's report, this study − among others − notes that IDF tumors often recur following excision [2, 11, 12]. Cases of ulcerated IDF nodules have been previously reported, though this presentation is not typical [13].

Fig. 1.

Multiple IDF nodules (a) and a solitary IDF nodule (b) demonstrating the classic smooth-surfaced, pink-red, domed presentation.

One case report [14] highlighted dermoscopic features of IDF. In their case of IDF of the right hallux, the authors noted telangiectasias in addition to what they referred to as “white dots” and “linear white constructions,” which were not found in other benign fibromatous conditions. It was hypothesized that the white dots represented fibrotic lesions, while the white constructions represented areas in which fibrosis and/or hyperkeratosis were most prominent [14]. In another case report of IDF on the dorsum of the foot, the authors employed ultrasonography as part of the evaluation and noted thickening of the subcutaneous soft tissue without signs of arteriovenous malformations or venous pockets [15].

One case series attempted to use plain film X-rays to characterize IDF nodules [6]. In this study, the X-rays were unremarkable, though some displayed soft tissue edema [6]. In a study of IDF utilizing magnetic resonance imaging [16], it was found that the tumors displayed a low signal intensity on T1-weighted sequences, while the signal could vary between low or high intensity when viewed using T2-weighted imaging. This variation in intensity of T2-weighted images seemed to have histopathologic significance, with low intensity corresponding to highly collagenous lesions and high intensity corresponding to highly cellular lesions [16]. Additionally, it was suggested that the use of magnetic resonance imaging may help elucidate what additional structures may be involved and may therefore guide treatment decisions.

The etiology of IDF remains unclear. In 1965, Reye initially suggested a viral cause [3], though a subsequent study in 1991 found no evidence of certain HPV strains (6, 11, 16, 18) or HSV types 1 and 2 in IDF specimens [17]. This study, along with successive ones that failed to detect any viral presence, showed that IDF pathogenesis can occur independently of viral infection. However, a recent case report found histopathologic signs of HPV infection, confirmed to be the low-risk HPV-4 strain on genomic testing, in a recurrent IDF patient whose grandmother had recently been diagnosed with verruca plana [18], suggesting that HPV may play a role in disease recurrence. Nogues et al. [19] also proposed that the mechanism may involve abnormal cellular metabolism due to defective fibroblast synthesis, though this mechanism has not been directly proven.

Histopathological Features

In Reye's original description of the histopathology seen in IDF [3], he described IDF as small tumors covered by an intact epithelium with growth restricted to the dermis. He proposed that as tumors continue to expand, they develop tongue-like extensions laterally and compress the epidermis, resulting in flattening of the rete ridges. Furthermore, Reye described round, pink cytoplasmic inclusion bodies that set these tumors apart from other fibrous tumors.

Recent descriptions of the gross and microscopic appearance of IDF nodules have described the appearance of unencapsulated [20], firm, rubbery masses composed of spindle cells arranged in whorled bundles with interlacing fascicles and broad storiform arrays (shown in Fig. 2) [2]. These tumors usually do not show mitotic activity [2], consistent with their slow growth and benign nature. Typically, the tumor cells surround adnexal structures and are present between periadnexal adipocytes [2]. Additionally, the aforementioned fascicles are often perpendicularly oriented [2]. Other common features include the presence of stromal mast cells, chronic perivascular and periadnexal lymphocytic infiltration, rete ridge flattening, and extension of tumor cells to the aponeurotic, fascial connective tissue, or joint capsule [2]. Using immunohistochemistry, the tumors express calponin, desmin, α-smooth muscle actin (shown in Fig. 3), and CD99 [2]. Some cells also express CD117, heavy caldesmon, CD10, nuclear β-catenin, and CD34 [2]. Additionally, the presence of microfilament bundles surrounding the inclusion bodies on immunohistochemical analysis suggests a possible myofibroblast origin for IDF tumors, separating them from other fibroblastic entities [2, 21].

Fig. 2.

IDF nodule histology (H&E) at ×20 (a) and ×60 (b), showing spindle cells arranged in whorled bundles with interlacing fascicles and broad storiform arrays.

Fig. 3.

IDF nodule histology staining positive for smooth muscle actin at ×60 (a) and ×400 (b).

In line with Reye's histopathologic description of IDF [3], follow-up studies support that the tumors typically develop cytoplasmic inclusion bodies [2]. Importantly, in situations where the eosinophilic inclusion bodies in IDF are difficult to detect by routine hematoxylin and eosin staining, phosphotungstic acid and hematoxylin can be used to stain the inclusion bodies purple (shown in Fig. 4) [22]. Additionally, the inclusion bodies stain bright red on both Masson's trichrome (shown in Fig. 5) and Lendrum's phloxine tartrazine and yellow with Elastica van Gieson staining [8]. It is important to note that although these inclusions are a key histopathologic feature [3], they are not identified in all cases [2].

Fig. 4.

IDF nodule histology at ×400 demonstrating inclusion bodies with H&E staining alone (a) and with PTAH staining (b), which stains them purple. PATH, phosphotungstic acid and hematoxylin.

Fig. 5.

IDF nodule histology with trichome staining at ×400, demonstrating inclusion bodies (stained red).

The precise composition of these inclusion bodies has not been determined. The inclusions can be highlighted using anti-calponin-1 antibodies, which suggests calponin-1 is either a component of the inclusions, or there is cross-reactivity of the antigens, indicating false positivity [19]. Electron microscopy has shown that the inclusion bodies contain 5–7 nm actin microfilaments [23], hypothesized to be cytoplasmic microfilaments trapped during the complex process of myofilament assembly [2], further supporting the categorization of IDF as a myofibroblastic tumor.

Treatment Options

Although some cases of spontaneous tumor regression have been noted [11, 24, 25, 26], various interventions, both surgical and nonsurgical, have been tried over the years (Table 1). Surgical intervention continues to be used to obtain tissue for diagnosis, but additional surgical intervention is now less favored [2, 24]. Additional surgery should be reserved for cases with functional impairment, maintained growth, or cosmetic concerns [2]. Even in the case of surgical management, disease recurrence is common within the first 2 years, with roughly a 74% recurrence rate following simple excision [2]. Observation alone is often recommended, though in rare cases, continued growth can involve neurovascular structures [27].

Table 1.

Summary of treatment data from past case series

Eypper et al. [28] propose a treatment algorithm including either (1) clinical observation or (2) a trial of intralesional chemotherapy or corticosteroids for stable asymptomatic cases. Specific recommendations include intralesional 5-fluorouracil injections of 0.2 mL at 50 mg/dL at 2–3 sites monthly for 5 months, and intralesional triamcinolone injections of 0.5–2 mL at 10 mg/mL with 1–3 injections over 5–40 months. Their study suggests reserving surgical excision for patients with large symptomatic nodules, or for nodules causing structural or functional disturbances [28]. Specifically, they recommend observation for asymptomatic nodules less than 1 cm, intralesional steroids or chemotherapy for asymptomatic lesions greater than 1 cm, and surgical excision for nodules causing pain, mobility changes, compromise of the overlying skin, or other structural deformities or dysfunction (Fig. 6).

Fig. 6.

Flowchart of clinical recommendations for treatment.

There is limited literature reporting the actual use and outcomes of intralesional steroid injections; one case report found no progression at 1 year after injection [29], and one retrospective study of 12 lesions found no statistical difference in the rate of recurrence between patients treated with surgical excision and those treated with intralesional corticosteroid, although the latter group had lower treatment-associated morbidity [30]. Topical therapies have also been tried. For example, topical imiquimod has been attempted with mixed results [31, 32]. The case with a successful outcome used imiquimod 5% cream 3 days per week in combination with methylprednisolone acetonate 0.1% ointment on the other days, achieving partial improvement by 8 weeks and near complete resolution by 22 weeks [31]. In another report, one in which impaired mobility spurred treatment, application of topical tacrolimus 1% ointment twice daily for 1 month resulted in improvement of the lesion by 2 months and complete resolution with restoration of mobility by 6 months [33].

Summary

IDF is a rare benign tumor that presents as a firm painless nodule on the digits of children and infants [2]. Originally described by Reye [3] in 1965, there have since been over 200 reported cases [1] as well as follow-up studies [2] further describing this condition. IDF has not been found to be associated with any viral etiology [17] and has not been associated with any genetic syndromes or medical conditions [8]. Clinically, IDF tumors are slow growing smooth, firm, and painless nodules [2] that typically spare the thumbs and great toes while primarily affecting the dorsal and lateral aspects of one of the remaining digits [2, 10]. Histopathologically, IDF is characterized by eosinophilic inclusion bodies which can be highlighted with special stains. The main treatment options include observation, intralesional corticosteroid or 5-fluorouracil injections, and surgical excision, though new topical options are being investigated. While there are no standardized treatment guidelines, Eypper et al. [28] recommend observation or intralesional corticosteroids for small, stable, asymptomatic nodules and reserving surgical intervention for lesions that are large, symptomatic, or affecting underlying structure or function.

Further identification of characteristic dermoscopic findings for IDF may decrease the need for biopsy for diagnosis. Studies of topical treatments, such as imiquimod and tacrolimus, are also needed. Additionally, a larger head-to-head comparison of intralesional corticosteroid or 5-fluorouracil injections with surgical excision would be helpful in guiding future treatment recommendations.

Statement of Ethics

Consent for photographs was obtained and documented per university protocol.

Conflict of Interest Statement

Joy Wan has received research and fellowship funding from Pfizer, Inc. for work unrelated to this manuscript.

Funding Sources

No funding sources.

Author Contributions

Rama Godse, Mohammed Dany, Shant Tamazian, and Adam Ian Rubin performed the literature review. Rama Godse, Mohammed Dany, and Shant Tamazian drafted the manuscript. Mohammed Dany and Adam Ian Rubin generated the pathology photomicrographs. Melinda Jen and Joy Wan contributed the clinical photographs. All authors interpreted the review data and revised the manuscript.

Funding Statement

No funding sources.