Keloids: An Update on Medical and Surgical Treatments

Keloids are the overgrowth of dense fibrous tissue that develops after healing of a skin injury. In 1806, Alibert used the term cheloide, derived from the Greek chele, or crab’s claw, to describe the lateral growth of tissue into unaffected skin.¹ Keloids extend beyond the borders of the original wound (ie, previous surgery, trauma, or acne), usually do not regress spontaneously, and tend to recur after excision (Figure 1). In contrast, hypertrophic scars typically do not expand beyond the boundaries of the initial injury and may undergo partial spontaneous resolution. Keloids occur more frequently in persons aged 10 to 30 years, with a higher proportion in individuals of African and Asian descent.² The most frequently involved sites of keloids are the earlobes, anterior chest, shoulders, and anterior neck, particularly areas of the body that are constantly subjected to high skin tension or trauma.

Despite their common occurrence, keloids remain one of the most challenging dermatologic conditions to successfully treat. More than a cosmetic nuisance, they are often symptomatic and can have a significant psychosocial burden for the patient.³

Compared with mature scar tissue, keloids have an increased blood vessel density, higher mesenchymal cell density, a thickened epidermal layer, and increased mucinous ground substance.⁴

The collagen in keloids is more irregular, abnormally thick, and has unidirectional fibers arranged in a highly stressed orientation.⁴ Collagenase activity, ie, prolyl hydroxylase, has been found to be 14 times greater in keloids than in both hypertrophic scars and normal scars. Collagen synthesis in keloids is 3 times greater than in hypertrophic scars and 20 times greater than in normal scars. Type III collagen, chondroitin 4-sulfate, and glycosaminoglycan content are higher in keloids than in both hypertrophic and normal scars. Collagen cross-linking is greater in normal scars, while keloids have immature cross-links that do not form normal scar stability. Keloids also have an increased number of fibroblasts, as well as mast cells, leading to a subsequent increase in histamine production.⁵

Immunohistochemical studies of keloids demonstrate that keloids have an increased production of tumor necrosis factor (TNF)–α, interferon (IFN)–β, and interleukin (IL)-6. Transforming growth factor (TGF)–β is crucial in the regulation of wound scarring. TGF-β1 and TGF-β2 expression leads to increased scarring, whereas expression of TGF-β3 reduces scarring. Proinflammatory cytokines IL-6 and IL-8 enhance scarring, whereas the anti-inflammatory cytokine IL-10 decreases the amount of scar tissue. Homeobox B13, the Wnt signaling pathway, early growth response1, and platelet-derived growth factor all favor fibroplasia.⁶ Unfortunately, no animal model exists for experimental investigation of keloids.

A strong genetic predisposition to formation of keloids is suggested by the increased prevalence in dark-skinned races, increased concordance among identical twins, and increased familial clustering.^2,7 In a familial study, 14 pedigrees with keloids spanning 3 to 5 generations were observed.⁸ They concluded that single gene mutations can predispose an individual to keloids and proposed an autosomal dominant mode of inheritance with incomplete clinical penetrance and variable expression.^2,9 It has been hypothesized that keloidal fibroblasts are an epigenetically distinct population. Keloid fibroblasts are resistant to hydrocortisone-induced downregulation of collagen and elastic; furthermore, the differential expression of several fibrosis-associated genes is specific to fibroblasts cultured from keloid nodules.¹⁰ A genome-wide linkage search for genes predisposing to keloid formation identified keloid susceptibility loci on chromosomes 2q23 for a large Asian family and on 7p11 for a large African American family.^2,9