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

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

Pathogenesis

• The exact pathogenesis of dermatofibroma is not completely understood.

• The mechanisms which are suggested in the pathogenesis of dermatofibroma include:
  • Reactive tissue changes
  • Neoplastic proliferation because of the clonality
  • The cell surface proteoglycan, syndecan-1, and fibroblast growth factor receptor 2 may play a role in the growth of dermatofibromas.
  • Transforming growth factor-beta (TGF-beta) signaling may be involved in the development of fibrosis in dermatofibroma
  • The presence of factor factor XIIIa and CD168 suggests that dermatofibroma can originate from dermal dendritic cell.

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]

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

Genetics

• There is no genetic alteration involved with pathogenesis of dermatofibroma.

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

Microscopically dermatofibroma is characterized by:

• Localized nodular proliferation of spindle-shaped fibrous cells in a mixture of histocytoid cells inside the dermis
• Spiculated margin of cells
• “Storiform” pattern which defines as whorls of elongated nuclei
• Collagen bundles that usually seen inside and between the fascicles of spindled fibrous cells
• "Grenz zone" which is an unaffected layer that separates the overlying epidermis from the dermis
• Epidermal hyperplasia