Multiple Dermatomyofibromas in a Patient with Ehlers-Danlos Syndrome

Abstract

Dermatomyofibromas are a rare, benign, acquired neoplasm with less than 150 reported cases worldwide. The etiologic factors that contribute to the development of these lesions are currently unknown. To our knowledge, there have been only six previously reported cases of patients presenting with multiple dermatomyofibromas, and in each of these cases, there were less than ten lesions present. Herein, we describe a patient who developed more than 100 dermatomyofibromas over a period of years, and we argue that the patient’s concurrent Ehlers-Danlos syndrome could have contributed to this unique presentation by inducing an increased fibroblast-to-myofibroblast transition.

Introduction

Dermatomyofibroma is a benign, acquired neoplasm composed of fibroblasts and myofibroblasts that is predominantly found in young adult females and children of either gender [1, 2]. It is not yet known what drives the development of this tumor, or what risk factors predispose patients to develop it. Patients tend to develop solitary lesions with a variable appearance, though the most common features include a superficial plaque or a circumscribed, oval, or annular nodule that can be tan, brown, or red in color [1, 3]. The heterogenous appearance of a solitary lesion means it is often mistaken for a hypertrophic scar, dermatofibroma, or dermatofibrosarcoma protuberans, and the appearance of multiple lesions further confounds a timely diagnosis and necessitates histopathology for confirmation [2, 3]. Ehlers-Danlos syndrome (EDS) is the name for a heterogenous group of diseases with varied underlying molecular mechanisms driving the disease but sharing several common symptomatic features [4]. We describe a patient who developed over 100 dermatomyofibromas in the context of EDS, which we argue could be a predisposing risk factor due to induced changes in fibroblast function. The CARE Checklist was completed by the authors for this case report and attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000530423).

Case Report

A 41-year-old patient with a past medical history significant for EDS, without subtyping at this time, initially presented to our clinic in 2012 for assessment of numerous spontaneously forming dark, indurated lesions across the chest. The patient reported that the initial lesions had taken a period of years to develop but, in the preceding months, had noted an increased rate of lesion formation. The patient reported that prior to lesion development, there was occasional pruritus or pain at the new site of formation but otherwise denied any associated symptoms.

On physical examination, numerous hyperpigmented, well-demarcated plaques were found scattered across the trunk, ranging in size and shape from 1 cm diameter round lesions to 2 cm × 14 cm linear lesions. Physical examination was otherwise unremarkable. The appearance of lesions on examination was consistent with keloids and hypertrophic scars, so the patient was agreeable to treatment with topical triamcinolone. Initial treatments proved modestly successful, so additional treatment modalities were attempted over a course of several years including topical clobetasol, topical pimecrolimus, and intralesional triamcinolone.

In subsequent appointments, the patient continued to develop additional lesions across the chest, abdomen, upper arms, and thighs, including a hypertrophic scar located over the sternum secondary to cardiac surgery. At this point, the patient had developed over 100 lesions since their initial presentation, though many of the lesions had regressed with time (Fig. 1). Following the sudden appearance of a serpiginous, hyperpigmented eruption on the upper abdomen, excisional biopsy was performed to rule out granuloma annulare. Histopathological examination showed epidermal hyperplasia and basal layer hyperpigmentation overlying a plate-like proliferation of fascicles of bland spindle cells with eosinophilic cytoplasm in the upper reticular dermis (Fig. 2a–c). The papillary dermis was uninvolved and there were few mitotic figures within the lesion. Immunohistochemistry showed that most lesional cells were weakly positive for smooth muscle actin (Fig. 2d) accompanied by focal positivity for factor XIIIa (Fig. 2e), but the lesions were negative for Sox-10 and desmin (images not included). These findings were consistent with a diagnosis of dermatomyofibroma, so three additional lesions were biopsied for comparison. Each biopsy demonstrated histopathologic and immunohistochemistry findings consistent with the first lesion, resulting in a final diagnosis of multiple dermatomyofibromas. At the time of this writing, no additional treatments have been pursued.

Fig. 1.

Clinical images demonstrating evolution of lesions over time in 2016 (a) and 2022 (b).

Fig. 2.

Histopathology for the skin biopsy, demonstrating epidermal hyperplasia and basal layer hyperpigmentation overlying a plate-like proliferation of fascicles of bland spindle cells in the upper reticular dermis (H&E, ×40) (a). b Higher power image of (a) (H&E, ×100). c Higher power image of (a) (H&E, ×400). d Immunohistochemistry highlighting the SMA-positive myofibroblasts within the lesion. Note that the small vessels also stain positive, which demonstrates a positive internal control (SMA, ×400). e Immunohistochemistry demonstrating scattered, non-specific positivity of factor XIIIa within the lesion (factor XIIIa, ×400). SMA, smooth muscle actin.

Discussion

Dermatomyofibromas were first described under the term plaque-like dermal fibromatosis in 1991 by Hügel but were later re-termed dermatomyofibroma in 1992 based on the histologic features present within lesions [3, 5]. Since this time, over 100 cases of dermatomyofibroma have been reported; however, there have only been six reported cases known to us where patients developed more than one dermatomyofibroma, and none reported numerous widespread lesions as seen with this patient, making this a unique presentation of the condition [1, 6–10].

The relative rarity of multiple dermatomyofibromas suggests there may be an underlying factor that predisposes patients to develop more than one lesion. In two of the six previous cases of multiple dermatomyofibromas patients had been previously treated for embryonic tumors, leading one group to hypothesize that embryonic tumors could serve as a driver for the development of multiple lesions because there is an upregulation of growth factors, fibrogenic cytokines, and signaling pathways with these tumors that can lead to myofibroblast proliferation [8, 10]. Our patient has never been diagnosed with an embryonic tumor, but she does have a past medical history significant for EDS. This led us to consider the possibility that EDS could be a potential risk factor for developing multiple dermatomyofibromas.

EDS is the name for a heterogenous group of heritable connective tissue disorders defined by shared traits of joint hypermobility, skin hyperextensivity, and tissue fragility, though the specific clinical picture for an individual varies based on the subtype of EDS they are diagnosed with as a consequence of different underlying causative mutations [4]. For example, both classical EDS and hypermobile EDS share many of the same clinical features including joint hypermobility, skin hyperextensivity, atrophic scarring, history of hernias, and a family history of EDS. However, while patients with classical EDS are found to have fragile, doughy skin and frequently experience easy bruising and papyraceous scarring, those with hypermobile EDS lack these features and instead are more likely to have arachnodactyly, pelvic organ prolapse, mitral valve prolapse, unexplained striae, and aortic root dilation [4]. Due to the different underlying mutations that define the individual subtypes of EDS, the pathogenesis of the disease and its effects on cellular function are not entirely understood, but a body of literature exists studying the effects of fibroblast activity and functionality in typical cases of classical, vascular, and hypermobile EDS. Both in vitro studies of cultured fibroblasts collected from patients and transcriptomic studies of patient samples demonstrate that fibroblasts derived from hypermobile EDS patients have a significantly increased propensity for fibroblast-to-myofibroblast transition [11, 12]. This is not observed in classical or vascular EDS. Histologically, dermatomyofibromas are defined by an increased abundance of myofibroblasts derived from fibroblast transition, so we argue that hypermobile EDS could predispose a person to develop dermatomyofibromas. More research will need to be done in this area to demonstrate a causal link between dermatofibromas and EDS, as well as the etiologic factors that underlie initial development of dermatomyofibromas. At the time of this writing, our patient was undergoing genetic workup to parse out their underlying subtype of EDS.

Management of dermatomyofibroma depends on age of the patient. It has been observed in children and adolescents that dermatomyofibromas will often spontaneously regress, so conservative management with monitoring and close follow-up is typically the treatment of choice [2]. In adult populations, there is no evidence showing that dermatomyofibromas spontaneously regress, so intervention is often pursued for cosmetic purposes [1, 3]. Simple excision has been shown to be extremely effective in preventing recurrence of lesions, even without clearance of margins [1, 3]. However, in the case of a patient such as ours, simple excision is not practical due to the size and widespread distribution of lesions making management difficult and largely focused on addressing symptoms associated with lesion development, including pruritus and pain.

Statement of Ethics

All the procedures adopted in this study followed the ethical standards of the World Medical Association Declaration of Helsinki. Ethical approval was not required for this study according to the local and national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

All funding for this research was provided by the SUNY Upstate Medical University Department of Medicine.

Author Contributions

Mark Lewis Derbyshire was responsible for preparation of this manuscript. Amy Leigh Brady was responsible for obtaining histopathologic images and editing of the manuscript. Ramsay Sami Farah was responsible for providing details pertinent to the case, editing of the manuscript, and providing patient care.

Funding Statement

All funding for this research was provided by the SUNY Upstate Medical University Department of Medicine.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.