The etiology of dermatofibroma remains controversial. There are several theories for the genesis of dermatofibromas: a reactive process and a neoplastic proliferation. Evidence exists for both of these theories.² Some patients report a history of local traumatic cutaneous insult such as insect bite, skin tattooing, skin injections such as tuberculin test or cosmetic filler, superficial puncture wound from thorns, or wood splinters, surgical trauma, and folliculitis, all of which argue for a reactive process. However, local trauma as a predisposing factor is inconsistent, and more commonly the lesions develop spontaneously without an inciting event.⁷,⁸,⁹,¹⁰,¹¹

Some authors have favored a clonal or neoplastic etiology,² and studies have identified clonal markers in dermatofibromas supporting a neoplastic process. Clonal proliferative growth has been shown in some dermatofibromas suggesting that they may represent a neoplastic process,¹² although clonality is not necessarily indicative of a neoplastic process and can be seen in some inflammatory conditions. One study proposed that dermatofibroma tumorigenesis may be due to distorted protein kinase C activity.¹³ Antibodies to factor XIIIa, which label dermal dendritic cells, are frequently positive in dermatofibroma.¹⁴ Spindle-shaped cells stain positively for HSP47, a marker for skin fibroblasts, suggesting that skin fibroblasts may be a major constituent of dermatofibromas.¹⁵ CD14⁺ monocytes have been proposed as the cell of origin of dermatofibromas.¹⁶

Transforming growth factor beta and other fibrinogenic factors have been reported to occur in high numbers in dermatofibromas¹⁷ and might serve as triggers of fibrosis.¹⁸ Some evidence suggests a role for the cell surface proteoglycan, syndecan-1,¹⁹ and fibroblast growth factor receptor 2, involved in epithelial-mesenchymal cross talk,²⁰ in the growth of dermatofibromas. Gene fusions have been described in dermatofibroma tumorigenesis.²¹,²² ALK gene rearrangement and overexpression have been demonstrated in both epithelioid and atypical variants of dermatofibroma.²³,²⁴

It has been proposed that eyelid dermatofibroma be considered related to, but distinct from, the classic dermatofibroma. This distinction was based on the unique dermal structure of the eyelids as well as eyelid-specific histopathological findings.²⁵

Dermatofibromas of the dermis clinically present as asymptomatic, slow-growing, nontender, firm, freely moveable reddish, yellowish, or tan cutaneous nodules (Figure 59.1).²⁶ Lesions usually are dome shaped, with a smooth or cystic appearance, and may have a central dimpling.²,²⁷,²⁸ They usually are relatively small, less than 1 cm in diameter.¹¹,¹⁴,²⁹,³⁰ Lesions are mostly solitary but may be multiple involving the eyelid and face.³¹

The differential diagnosis of dermatofibroma includes a wide variety of benign cutaneous lesions.³²,³³ These include acrochordon, atypical fibroxanthoma, nevus, cutaneous
melanoma, cutaneous lipoma, juvenile xanthogranuloma, neurilemmoma, leiomyoma, and pilomatrixoma. More importantly, the differential can include malignant lesions such as basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, Merkel cell carcinoma, and T-cell lymphoma. It is important to distinguish benign dermatofibroma from dermatofibrosarcoma protuberans (DFSP). These two lesions have a similar appearance but DFSP is a more aggressive cutaneous neoplasm.⁴,¹²,³⁴ DFSP is usually larger, and more commonly involves the subcutis. Immunohistochemical staining can be very helpful in distinguishing it from benign dermatofibroma. Kaposi sarcoma may be mistaken for the aneurysmal variant of dermatofibroma. Basal cell carcinomas can mimic dermatofibroma clinically and histologically.³⁵,³⁶,³⁷,³⁸