The treatment of hypertrophic scars and keloids

ARTICLE

Keloids are proliferative dermal growths that develop after skin injury. Unlike hypertrophic scars, the scar tissue extends beyond the borders of the original wound. The first description of keloids was offered in the Smyth papyrus on surgical techniques in Egypt 1700 BC [1]. Subsequently, Alibert in 1806 used the term "cheloide", derived from the Greek "chele" or crab claw to describe the lateral growth of tissue into normal skin [2]. In addition to the cosmetic disfigurement these scars represent to affected patients, they can be pruritic, tender and can be complicated by secondary infections.

Keloids occur most commonly between the ages of 10 and 30 years [3]. Deeply pigmented people are more susceptible to proliferative scarring than those with fair skin. Keloid formation correlates with sites where melanocyte concentrations are greatest [4]. In addition, pregnancy and puberty, times of increased physiologic pituitary activity, have been associated with increased keloid formation [4]. Incidence has been reported at 4.5 and 16% in black and Hispanic populations respectively [5]. Definitive incidence figures are not known for hypertrophic scars. Inheritance patterns of keloids are autosomal dominant and autosomal recessive and they have been genetically associated with HLA B14, B21, Bw16, Bw35, DR5, and DQw3 [3, 6, 7].

Keloids differ from hypertrophic scars clinically and histologically [8-12]. Clinically, keloids are a deep red or purple color with raised indurated tissue that extends beyond the original wound borders. Hypertrophic scars have a less impressive white or pink color, with firm tissue limited to original wound border. Histologically, keloids are composed of disorganized thick hyalinized collagen with a prominent mucoid matrix, whereas hypertrophic scars are characterized by fewer, more organized collagen fibers with a scanty mucoid matrix. The fibroblast concentration is more prominent in hypertrophic scars [8-12].

The exact pathophysiological factors for excessive scarring are unknown. Increased skin tension has been cited to play a role in presternal, back and deltoid regions [13]. Fibroblasts have been shown to produce more collagen under tension. However, this relationship is not universal as keloids commonly occur in earlobes, an area typically free of tension.

The distinct biochemical composition of keloids and hypertrophic scars includes an increased rate of proline hydroxylase activity, a marker of collagen synthesis. Keloids exhibit 20 times the rate of collagen synthesis of normal skin and three times the rate of hypertrophic scars. This increased level normalizes after two to three years [10, 14-19]. Increased turnover of scar tissue is evident by increased collagenase activity, however, this is not enough to overcome the increased synthetic activity. An increased concentration of chondroitin-4-sulfate is also found, which can coat collagen fibers making them less susceptible to collagenase activity [10, 14-19].

Management

Numerous therapeutic options for the treatment of keloids and hypertrophic scarring will be discussed. Keloid and hypertrophic scar therapy ranges from the less aggressive topical dressings and pressure modalities to the more aggressive radiotherapy, cold knife or laser excision. The reader should be aware of a number of shortcomings in some of the literature dealing with the management of proliferative scarring: a) Some studies report on a small number of lesions or patients. b) The follow-up in some studies is less than one year. c) Occasionally, when evaluating treatment efficacy, a clear definition of what constitutes a significant objective response is not reported. d) The duration and prior treatments of the lesions under study are not routinely discussed. e) There is lack of clear separation between hypertrophic scars and keloids.

Occlusive dressings

Occlusive dressings such as silicone gel sheets and silicone occlusive sheeting have been used with varied success [3, 20, 21]. Silicone gel sheets are applied to hypertrophic and keloid scars for 12 hrs or more a day. One controlled study reported a zero percent complete resolution with more than 75% of the patients obtaining minimal to no improvement over untreated control sites [20]. A more favorable response was obtained in a study of 20 hypertrophic scars and keloids treated with silastic dressing [22]. Complete resolution was reported in 6 out of 20 patients, and 9 out of 20 patients were graded as having a good response to therapy. There were no traces of silica detected in tissue sample analysis of treated patients. Post-operative use of silicone gel sheeting also showed efficacy in a separate study of eight keloids with a 12.5% recurrence rate compared with 37.5% in the excision only group [23].

It can be generally concluded that occlusion and hydration are the principal factors leading to anti-keloidal effects rather than silicone [24, 25]. A water-impermeable, non-silicone-based occlusive dressing worn continuously for two months brought about an average keloid height reduction of 35% after eight weeks in 19 out of 21 patients. Furthermore, a reduction of pain, pruritus and erythema was noted in the majority of patients [25].

Compression

Pressure has long been known to have thinning effects on the skin. Reduction in the cohesiveness of collagen fibers in pressure-treated hypertrophic scars has been shown by electron microscopy [26]. A reduction in fibroblast content, total chondroitin-4-sulfate content, probably mediated by local tissue hypoxia induced by pressure-treated scars are additional mechanisms by which this modality reduces excessive scarring [26-28]. Button compression, two buttons sandwiching the earlobe applied after excision of a keloid, resulted in no recurrence at eight months to four years of follow-up [29].

Other pressure devices include pressure earrings and pressure gradient garments made of light-weight, porous Dacron spandex bobbinet, usually worn 12 to 24 hrs per day, and zinc oxide adhesive plaster. There was a 75 to 100% improvement in 60% of patients treated with these various devices [30-32].

Corticosteroids

Intralesional corticosteroids have been the mainstay of treatment. Corticosteroids reduce excessive scarring by reduction of collagen synthesis, glucosaminoglycan synthesis, and a reduction in inflammatory mediators and fibroblast proliferation during wound healing. The most commonly used corticosteroid is triamcinolone acetonide (TAC) in concentrations of 10 to 40 mg/ml administered intralesionally with a 25-27 gauge needle at four to six week intervals. The efficacy of intralesional corticosteroids alone and adjunctive to excision in the treatment of hypertrophic scars and keloids has been shown in various studies [33-37]. Response rates have varied between 50-100% with recurrences of 9 to 50% in completely resolved scars. Less commonly used, dexamethasone 21-phosphate 1 mg/ml intralesionally yielded a 76.5%, good to excellent response [38]. When combined with excision, post-operative intralesional TAC injections yield a recurrence rate of 0-100% with the majority of studies citing less than 50% recurrence [39]. Complications of repeated corticosteroid injections include atrophy, telangiectasia formation and pigmentary alterations.

Cryosurgery

Cryosurgical media such as liquid nitrogen, affect the microvasculature and causes cell damage via intracellular crystals leading to tissue anoxia. Generally, one to three freeze-thaw cycles lasting 10-30 sec are used for the desired effect. As a single modality, cryosurgery caused complete resolution with no recurrence in 51-74% of patients after 30 months of follow-up [40]. Treatment may need to be repeated every 20-30 days. Cryotherapy in combination with intralesional corticosteroids yielded "excellent results" after 1.5 years [41].

Excision

Basic soft tissue handling techniques should be applied at primary wound repair. Careful planning of closure with minimal tension should be used paralleling relaxed skin tension lines. Buried sutures should be employed when necessary for layered closure and to reduce tension. However, they should be kept to a minimum to prevent excessive presence of foreign material during the proliferative and remodeling phases of wound healing. Likewise, tissue undermining should be done when absolutely necessary for a tension free closure, as extensive undermining could potentially expand the field for keloid formation. When feasible, pressure dressings and garments can be applied during the immediate post-operative period in the wounds of patients subject to hypertrophic scars and keloid formation [42]. Excision surgery alone yields a 45-100% recurrence rate. Decreased recurrence rate is consistently reported with excision in combination with some other post-operative treatment modality such as radiotherapy, intralesional interferon or corticosteroids.

Radiation therapy

The management of keloids using radiotherapy remains a controversial issue. Even though numerous studies have demonstrated efficacy as well as decreased recurrence rates, the safety of this modality has been questioned. In one retrospective study of superficial X-ray therapy of 24 excised keloids, the author reported a recurrence rate of 53% [43]. In spite of using a carcinogenic agent such as radiotherapy to treat a benign process such as keloids, no single unequivocal causal effect for carcinoma was found according to the author's review.

External radiation of keloids utilizing different dosage regimens had significant objective response rates of 16-94% [39, 44]. The use of iridium-192 interstitial irradiation after excisional surgery resulted in a 21% recurrence after one year [45]. In a comparative prospective study of post-operative radiotherapy versus corticosteroid injections, 12.5% of irradiated sites versus 33% of the injected sites recurred [46]. Importantly, no patient in any treatment group had compromised wound healing, chondritis or pigmentary alterations. Excisional surgery and pre-operative hyaluronidase solution 150 U/ml NaCl followed by external radiation 720-1,080 rads, resulted in zero percent recurrence [47]. In a study of sternal keloids treated surgically followed by skin grafting, post-operative radiation to the suture line and periodic steroid injections, the recurrence rate was 9% after a follow-up in some patients of up to 24 years [48].

Laser therapy

Ablation of keloid and hypertrophic scar with carbon dioxide laser (10,600 nm) has been widely studied. The carbon dioxide (CO₂) laser can cut and cauterize creating a dry surgical environment with minimal tissue trauma [49-51]. Unfortunately, the results using this modality vary and do not depict a clear advantage over cold steel excision. Recurrence rates have ranged between 39-92% [39, 49, 50, 52-55]. When combined, carbon dioxide laser and post-hyaluronidase offered a 16% recurrence rate after three years [51]. Combination of CO₂-laser followed by cryosurgery is also effective. The Nd:YAG (1,064 nm) laser has been shown to decrease collagen production in vitro [56]. Clinically, efficacy has been demonstrated in scar reduction, decreasing erythema and induration; however, recurrence rates using this modality have been reported between 53-100% [39, 56]. The Argon (488 nm) laser, similarly to the CO₂ laser, can induce collagen shrinkage via generation of excessive localized heat. In a small series, recurrence rates varied from 45-93% [39, 57, 58].

The pulsed-dye laser (585 nm) provides photothermolysis leading to microvascular thrombosis. Beginning in the 1980's it was noted that scars became less erythematous, more pliable and less hypertrophic after treatment with the 585 nm pulsed-dye laser. These findings were later confirmed with objective measurements of erythema by reflectance spectrometry readings, scar height and pliability measurements. Sixteen patients treated with the pulse dye laser for their sternotomy scars benefited from decreased pruritus, erythema and scar height [59].

Interferon therapy

A novel idea in the treatment of keloids and hypertrophic scars is the use of intralesional interferon. In vitro studies have demonstrated that interferons-alpha, -ß, and -gamma reduce keloidal fibroblast production of collagen I messenger RNA. Interferon-alpha, in addition, has been shown to increase collagenase activity [60]. In one study, six out of eight patients had a decrease average height of their keloids of 31% compared to 1.1% in controls [61]. Larrabe et al., in a study of 10 patients treated with intralesional interferon gamma 0.1 mg and 0.01 mg showed decreased height in 10 out of 10 patients, with 5 out of 10 patients benefiting from a greater than 50% decrease in scar height [62]. Interferon injected into the suture line of keloid excision sites may prophylactically reduce recurrences. Berman and Flores reported statistically significantly fewer keloid recurrences in a study of 124 keloids after post-operative interferon-alpha 2_b (10 mU/cc diluent; 1 million units/linear cm of suture line) injected into keloid excision sites (18%) versus keloids excised alone (51.1%) and TAC-treated sites (58.4%) [63].

Potential therapies

Additional potential therapeutic options for hypertrophic and keloidal scarring shown in vitro to affect collagen synthesis include: proline-cis-hydroxyproline and azetidine carboxylic acid [64, 65], tranilast, an anti-allergic drug shown to decrease both collagen and glycosaminoglycan synthesis [66], and pentoxifylline, an inhibitor of DNA replication [67, 68]. Furthermore, wounds treated with anti-TGF-ß healed with minimal scar tissue formation without affecting wound tensile strength [69]. A possible candidate by virtue of its neutralizing effect on TGF-ß, is the proteoglycan, Decorin [69].

Hypertrophic and keloidal scarring is more common in darkly pigmented races. There is increased proliferative scarring during increased hormonal stimulation.

Keloids are characterized by more disorganized, thickened collagen fibers and a prominent mucoid matrix.

It is generally thought that tension plays a major pathophysiological role in the development of proliferative scarring. However, keloids commonly develop in tension-free areas such as the earlobe.

It can be generally concluded that occlusion and hydration are the principal factors leading to anti-keloidal effects rather than silicone.

One study reported a 75 to 100% improvement in 60% of patients treated with these various pressure devices.

When combined with excision, post-operative intralesional TAC injections yield a recurrence rate of 0-100% with the majority of studies citing less than 50% recurrence.

Wound closure with minimal tension should be used, paralleling relaxed skin tension lines. Buried sutures should be kept to a minimum to prevent excessive presence of foreign material during the proliferative and remodeling phases of wound healing. Likewise, tissue undermining should be done when absolutely necessary for a tension-free closure.

External radiation of keloids utilizing different dosage regimens had significant objective response rates of 16-94%. In spite of using a carcinogenic agent such as radiotherapy to treat a benign process such as keloids, no single unequivocal causal effect for carcinoma has been reported.

Intralesional interferon-g and -a 2_b have been used successfully to decrease scar height and reduce the number of post-operative recurrences.

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