Dermatofibroma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Homa Najafi, M.D.[2]Faizan Sheraz, M.D. [3]

Overview

Dermatofibromas are composed of disordered collagen laid down by fibroblasts.

Pathophysiology

• Dermatofibromas form as a reaction to previous injuries such as insect bites or thorn pricks. Dermatofibromas are composed of disordered collagen laid down by fibroblasts.

Immunohistochemical staining

Neoplasm	CD34	Stromelysin-3	Factor XIIIa
Dermatofibroma	+	+	+
Dermatofibrosarcoma protuberans	+	-	-

Overview

The exact pathogenesis of [disease name] is not fully understood.

OR

It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].

OR

[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

OR

Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

OR

[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].

OR

The progression to [disease name] usually involves the [molecular pathway].

OR

The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathophysiology

Physiology

The normal physiology of [name of process] can be understood as follows:

Pathogenesis

• The exact pathogenesis of [disease name] is not completely understood.

OR

• It is understood that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
• [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
• Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
• [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
• The progression to [disease name] usually involves the [molecular pathway].
• The pathophysiology of [disease/malignancy] depends on the histological subtype.

Dermatofibromas have many histologic variants including cellular, epithelioid, lipidized, aneurysmal, monster cell, and atypical (to name only a few); but the most frequently diagnosed is the common fibrous histiocytoma or common dermatofibroma.

The common dermatofibroma is characterized histopathologically by a localized proliferation of spindle-shaped fibrous cells admixed with histiocytoid cells within the dermis. This proliferation is usually nodular in appearance, with spiculated, but moderately defined, borders that may have a pushing appearance in regards to the surrounding tissue. The spindle cells will form focally what is referred to as a “storiform” pattern, which describes a multi-centric whorling appearance of the elongated nuclei. There may be intermixed capillaries and lymphocytes or multinucleated giant cells. These proliferations are usually contained within the dermis, but it is not uncommon to observe a small portion of the lesion dipping down into the subcutaneous tissue along septal lines. A helpful and distinguishing characteristic is the presence of trapped collagen bundles or “collagen balls” within and between the fascicles of spindled fibrous cells. These entrapped collagen collections are more commonly found forming at the periphery of the lesion.

The overlying epidermis is usually separated by a clearly delineated and unaffected zone of separation, the "Grenz zone." Typical reactive epidermis changes include hyperkeratosis and acanthosis. The epidermis also will often exhibit elongated rete ridges diving into the dermis with hyperpigmented basal keratinocytes, which is referred to as the “dirty feet” sign.

Arguably the most important entity to distinguish dermatofibromas from is the similar appearing, but much more worrisome, dermatofibrosarcoma protuberans (DFSP). These lesions are more typically much more cellular, have a more marked development of the storiform pattern, and will invade and involve the subcutis much more deeply, often entrapping fat as it dives and proliferates along the subcutaneous septae

The precise mechanism for the development of dermatofibroma is unknown. Rather than a reactive tissue change, evidence that dermatofibroma may be a neoplastic process is demonstrated by its clonal proliferative growth. [2] Clonality, by itself, is not necessarily synonymous with a neoplastic process; it has been demonstrated in inflammatory conditions, including atopic dermatitis, lichen sclerosis, and psoriasis. Dermatofibroma tumorigenesis may be due to distorted protein kinase C activity. [3]

Results from immunohistochemical testing with antibodies to factor XIIIa, which label dermal dendritic cells, are frequently positive in dermatofibroma, while antibodies to MAC 387, which label monocyte-derived macrophages (histiocytes), show less consistent results. One study evaluated the expression in dermatofibroma of HSP47, a recently used marker for skin fibroblasts; CD68, a marker for histiocytes; and factor XIIIa. Most of the spindle-shaped cells in all 28 cases of dermatofibroma, irrespective of histologic variant, stained positively with HSP47, indicating that skin fibroblasts are a major constituent of dermatofibroma. Factor XIIIa–positive dendritic cells also are present, but the presence of CD68-positive histiocytes was inconsistent, especially between histologic variants. [4] CD14+ monocytes have been proposed as the cell of origin of dermatofibromas. [5]

The cell surface proteoglycan, syndecan-1, [6] and fibroblast growth factor receptor 2, involved in epithelial-mesenchymal cross-talk, [7] may play a role in the growth of dermatofibromas. Transforming growth factor-beta (TGF-beta) signaling might be a trigger of the fibrosis seen in dermatofibromas. [8] TGF-beta, along with other fibrinogenic factors, may be produced by mast cells, which have been reported to occur in abnormally high numbers in dermatofibromas. [9]

Gene fusions have been described in dermatofibroma tumorigenesis. [10, 11] ALK gene rearrangement and overexpression has been demonstrated in the epithelioid and atypical dermatofibroma variants

The precise cell of origin of dermatofibroma has long been disputed. The contemporary hypothesis is that the tumor originates from dermal dendritic cells (dendrocytes) of monocyte/macrophage lineage.4,5,27,29,32,36e38 Whether a cell adopts a dendritic or spindled configuration in the confines of the extracellular matrix depends on the latter’s composition and deformational capacity. The delicate dendritic processes are outlined by factor XIIIa and CD168 immunostaining. The monster cells are nonstaining, indicating that they may be effete or degenerating forms. Cytoplasmic staining for factor XIIIa has long been regarded as the preeminent hallmark of the constituent dermal dendritic cells.4,5,35,37 Factor XIIIa is synthesized, but not secreted, by monocytes of bone marrow origin. It is not a property narrowly confined to dermal dendritic cells, with which it is therefore not synonymous. 27,29,34,36,37 It is a transglutaminase heterotetramer activated by thrombin that leads to the formation of an insoluble clot conducive to a renewal of stromal assembly. Factor XIIIa together with CD163 denote a lineage from monocytes (bone marrow derived).Indeed, given the range of cellular morphologies in dermatofibromatous lesions and the different immunophenotypes of the participating cells, this diagnostic rubric probably embraces lesions at different stages of, and with different pathways for, their evolution. Included in these processes is the recruitment of secondary inflammatory cells or their activation through the effects of chemokines and cytokines. The resultant cellular typologies are mixtures of plump polyhedral histiocytoid cells/epithelioid cells, which in dermatofibromas may have a heterogeneity of origins. The coparticipation of myofibroblastic spindle cells can create a storiform pattern. How lesions of different cellular phenotypes are gathered together and governed architecturally remains unknown. On the other hand, an almost totally epithelioid cell proliferation devoid of a salient spindle/ fascicular cell component has been characterized among dermatofibromas over the past 20 years.1,10,16,20,23,35 This variant can simulate a Spitzoid melanoma or Spitz nevus,31 except for the absence of junctional nests. Melanocytic biomarkers (MART-1, HMB45, MiTF) can assist in resolving this diagnostic dilemma. Dermal dendritic cells (dendrocytes) typically reside in a close microanatomic relationship to the pericapillary space (endothelium-related cells). They are thought to be the source of many dermatofibromas23,32,35 and belong to the dermal microvascular unitda plexus in the upper reticular and papillary dermis. The dendrocytes function as an adventitial pool of reserve or stem cells. This complex microvascular structure also includes monocytic/histiocytic cells. Nonproliferative dermal dendritic cells are CD34þ, but this biomarker expression is lost if the cells proliferate or differentiate. This situation is also found in corneal stromal cells (keratocytes), which are CD34þ in a resting phase but become CD34� in corneal scar formation or fibrous downgrowth.14 The loss of CD34 expression which plays a role in intercellular adhesion allows the cells to migrate. Dendritic morphology alone, however, should not obscure the fact that dendritiform cells offer a multiplicity of molecular/ biochemical phenotypes: some express factor XIIIa, whereas others bear CD163þ monocyte/macrophage phenotypes29,37 or are CD1aþ Langerhans cells.35 The last cell type together with indigenous dermal dendritic cells is example of antigen-processing cells manifesting major histocompatibility complex class-II molecules.26,35 In the lesion reported herein, Langerhans cells and phagocytic histiocytes were commingled, a feature also discovered in eyelid perilymphatic granulomas of the Melkersson-Rosenthal syndrome.7 The interplay of these disparate cells probably plays a central role in the development of the lesions and may reflect a distinctive organization and immunologic pattern of the eyelids. Some have concluded that, rather than being a low-grade neoplasm, dermatofibroma might well represent an abortive immunoreactive process triggered by dermal dendrocytes.26

Stereotypical Histology DFs show a dense infiltrate of fibrocytes and/or macrophages in the reticular dermis, and, sometimes, the upper part of the subcutis. Early lesions are rich in macrophages, some of which may be siderophages, and/or lipophages, others multinucleate, e.g., Touton or foreign body giant cells. At times foam cells may be prominent in deeper areas adjacent to subcutaneous fat. Late lesions (Fig. 2) show prominent fibrocytes and coarse bundles of collagen in a haphazard fashion, frequently arranged in short fascicles that interweave (“storiform“), sometimes with a sclerotic center. Lesions are ill defined owing to splaying of both fibrocytes and macrophages between thickened collagen bundles at the periphery of the lesion (often called ”entrapment of collagen”). Epidermal, melanocytic, and folliculosebaceous hyperplasia is characteristically found above the lesions, while rarely smooth muscle or neural proliferation is observed [30]. The epidermal hyperplasia is most common and can be so prominent that buds of hair follicles mimic superficial basal cell carcinoma [31]. It may be minimal or absent in late or deep-seated lesions. Lymphocytes are often spread throughout the lesion with frequent prominence at the periphery but may be lacking in later stages. Histologic Variants A wide variety of histologic variants of DFs has been proposed [32]. Apart from unusual architecture, as alluded to under clinical variants (Figs. 3, 4), DFs may present with stromal and cellular peculiarities. Antler- to staghorn-like vascular ectasia in a lesion with dense cellularity has been described as hemangiopericytoma-like fibrous histiocytoma [33]. In other instances lamellar and storiform fibrosis surrounded by palisades of fibrocytes mimics schwannoma. This has been described as palisading dermatofibroma of the hands and feet, where such lesions are most frequently encountered [34]. Similarly, myxoid dermatofibromas [35,36] (Fig. 5) are most commonly seen on the hands and feet, in particular on the fingers and toes. Such lesions reveal the typical silhouette of a DF, yet the collagen bundles are less thick and storiform, but separated by vast amounts of mucin. There may be some relation to mucous cyst of the finger, which may be another trigger of a DF-like response. Rare cases of ossifying dermatofibroma reveal bone formation with osteoclast-like giant cells [37]. In our experience subungual osteochondroma (syn-onyms: subungual exostosis and fibro-osseous pseudotumor of the digit) [13] overlaps with or is intimately connected with subungual or acral counterparts of dermatofibroma. Peripheral ossifying fibroma in the oral cavity is a DF-like lesion that invariably contains bone. The special anatomy with bone and cartilage close to the skin or mucosa and the susceptibility to trauma are responsible for the involvement of these components in otherwise typical fibrosing inflammation. The various types of superficial fibromatoses [13] such as palmar Dupuytren contracture, plantar Ledderhose disease, or penile Peyronie contracture all share features with DF. They can be interpreted as late-stage variants of such a fibrosing process complicated by the sequelae of shrinkage. In contrast, in the subcutis or deeper tissues the more loose tissue conditions give rise to other presentations: “connective tissue culture”-like appearance in nodular fasciitis; or with epithelioid, sometimes giant cells with homogenous cytoplasm (“ganglion”-like cells) in proliferative fasciitis; or with analogous features in deep muscle tissue as proliferative, sometimes ossifying myositis [13]. Unusual cytologic features of DFs include epithelioid cell histiocytoma [17,38] with scalloped eosinophilic cells, which may mimic Spitz or other types of nevi, yet never express melanocytic markers such as S100 protein, HMB45, or Melan A (A103). It has been suggested [17] that the location in the papillary dermis with a moderate amount of loose collagen fibers allows cells more easily to develop epithelioid features than in the reticular dermis where the much more restricted tissue constrictions favor a spindle-cell appearance. Alternatively, the age of a lesion may play a role, so that early phases show epithelioid fibroblasts, whereas in later stages spindle cells are seen. While most of these lesions are confined to the papillary dermis with a prominent collarette of epidermis and adnexal epithelium lateral to the exophytic papule, some lesions can extend deeply into the reticular dermis and even subcutis, either diffusely or with fascicles or nests. In our experience such deep penetrating epithelioid cell histiocytomas (Fig. 6) are part of the spectrum known in the literature as cellular or atypical benign fibrous histiocytoma [39], most commonly located on the trunk, back, and upper arm, and frequently misinterpreted as fibro-, leiomyo- or even angiosarcomas, the latter in particular when additional hemorrhage is prominent. In clear cell dermatofibroma [40,41] (Fig. 7), epithelioid fibrocytes show an ill-defined, empty cytoplasm interspersed by thickened collagen bundles. Together with epidermal and melanocytic hyperplasia and some moderate lymphocytic response, this gives the vague silhouette of a DF. Because of prominent vascularization, such lesions are frequently thought to represent metastases from renal cell carcinoma. They are negative for keratin markers. Some clear cell DFs focally show a PAS-positive granular cytoplasm akin to that of granular cell dermatofibromas [42]. The latter occur predominantly on the shoulder girdle and are indistinguishable from “ordinary” granular cell tumors except that they stain negative for S100 protein. Fibrocytes are epithelioid and show a prominently granular eosinophilic cytoplasm with considerable variation in the size of granules, some of which measure nearly half the size of erythrocytes. Again architectural criteria of collagen entrapment, epidermal and melanocytic hyperplasia, and a moderate infiltrate of demarcating and intermingled lymphocytes, as well as the S100 protein negativity, are helpful for diagnosis. Apart from all these individual variations, some lesions may show a combination of several unusual clinical and histopathologic features, e.g., deep penetration and epithelioid cells (Fig. 6); recognition of such combined dermatofibromas [15] allows the histopathologist to apply a confident benign label to unusual lesions.

Genetics

• There is no genetic alteration related

Associated Conditions

Conditions associated with multiple dermatofibromas include:

• Pregnancy
• Chromosomal alterations (Down syndrome)
• Metabolic disorders (hypertriglyceridemia)
• Hematologic malignancies
• Immunodeficient diseases (HIV)
• Autoimmune diseases (myasthenia gravis, Pemphigus vulgaris, and systemic lupus erythematosus)

Gross Pathology

On gross pathology, firm yellowish papules which may have areas of hemorrhage and lipidization are characteristic findings of Dermatofibroma.

Microscopic Pathology

On microscopic histopathological analysis, localized proliferation of spindle-shaped fibrous cells in combination with histocytoid cells inside the dermis, [feature2], and [feature3] are characteristic findings of [disease name].

The common dermatofibroma is characterized histopathologically by a localized proliferation of spindle-shaped fibrous cells admixed with histiocytoid cells within the dermis. This proliferation is usually nodular in appearance, with spiculated, but moderately defined, borders that may have a pushing appearance in regards to the surrounding tissue. The spindle cells will form focally what is referred to as a “storiform” pattern, which describes a multi-centric whorling appearance of the elongated nuclei. There may be intermixed capillaries and lymphocytes or multinucleated giant cells. These proliferations are usually contained within the dermis, but it is not uncommon to observe a small portion of the lesion dipping down into the subcutaneous tissue along septal lines. A helpful and distinguishing characteristic is the presence of trapped collagen bundles or “collagen balls” within and between the fascicles of spindled fibrous cells. These entrapped collagen collections are more commonly found forming at the periphery of the lesion.

The overlying epidermis is usually separated by a clearly delineated and unaffected zone of separation, the "Grenz zone." Typical reactive epidermis changes include hyperkeratosis and acanthosis. The epidermis also will often exhibit elongated rete ridges diving into the dermis with hyperpigmented basal keratinocytes, which is referred to as the “dirty feet” sign.

Arguably the most important entity to distinguish dermatofibromas from is the similar appearing, but much more worrisome, dermatofibrosarcoma protuberans (DFSP). These lesions are more typically much more cellular, have a more marked development of the storiform pattern, and will invade and involve the subcutis much more deeply, often entrapping fat as it dives and proliferates along the subcutaneous septae.