Keloids: A Review of Etiology, Prevention, and Treatment

Abstract

Keloids are abnormal scars that cause significant emotional and physical distress in patients when inadequately treated. Keloid formation is theorized to occur as a result of an imbalance between an increased synthesis of collagen and extracellular matrix and decreased degradation of these products. Inflammatory mediators— namely, transforming growth factor beta—have been proposed to influence the dysregulation of collagen remodeling in the scar healing process. Though limited, current knowledge of keloid pathophysiology has guided clinicians to explore novel therapies for keloid prevention and treatment. In addition to conducting research refining the use of common therapies, such as steroids and radiation, clinicians have evaluated the potential of anti-inflammatory and chemotherapeutic molecules to suppress keloid recurrence. Procedural focused therapies, such as cryotherapy and lasers, have also found a role in reducing keloid symptomatology. The purpose of this report is to examine the current literature and review the mechanisms of action, efficacy, and side effects of different keloid therapies. Despite the growing literature investigating reliable methods for keloid management, there are no standardized guidelines or treatment protocols supported by academic governing bodies. Stronger evidence with high-fidelity randomized clinical trials will be needed to determine the optimal therapy regimens for keloids.

The primary goal in the clinical management of skin wounds, whether unintended or iatrogenic, is to aid the natural dynamic process of wound healing to re-establish baseline skin integrity, function, and aesthetics. Scar formation occurs over distinct phases, including hemostasis, inflammation, proliferation, and remodeling.1 After injury to the skin, exposed elements in various layers of the skin, in addition to vasoactive and inflammatory chemical mediators, contribute to clot formation for hemostasis and attract inflammatory cells to the site for the inflammatory phase.2 Key chemical mediators include transforming growth factor beta (TGF-β), interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), and vascular growth factor (VEGF).2 In this phase, neutrophils are the first to be seen active at the injury site to rid the area of debris and possibly infectious material.1 The inflammatory phase occurs over, on average, three days.1 Additionally, different subtypes of leukocytes that secrete growth factors, as well as chemotactic proinflammatory cytokines that recruit cell types needed for the proliferative phase, are also present in this phase.1,2 Endothelial cells, macrophages, and fibroblasts are present to help create granulation tissue, new vasculature, and the extracellular matrix (ECM) that will replace clot in the wound and help migrating cells adhere and function.2 Within the ECM, Type III collagen is present at this stage of healing. Next, re-epithelization occurs due to the recruitment of keratinocytes.2 The proliferative phase will occur over subsequent weeks.1 Then, fibroblasts convert into myofibroblasts, which are responsible for wound contracture.3 The final healing phase is remodeling. During the remodeling phase, the ECM and granulation tissue degrade via proteases, while mature Type I collagenous matrix and scar tissue form.3 Furthermore, vascular cells and the myofibroblasts degrade in an organized fashion.3 The balance of synthesis and the disintegration of cell types is essential to provide optimal wound healing.1–3 The remodeling phase occurs over months.1 A deviation in any phase of healing can result in aberrant and sometimes excessive scar formation.1–3

KELOIDS AND HYPERTROPHIC SCARS

Keloids and hypertrophic scars are two well-known types of excessive pathologic scarring. These types differ by aesthetics, pathogenesis, histopathology, and treatment, although there are overlapping characteristics. Compared to hypertrophic scars, keloids are characterized as more clinically severe in nature, causing pruritus and pain more frequently in patients.4 Classically, keloid scars appear slowly over months beyond the initial wound edges, while hypertrophic scars typically develop over a period of weeks and stay within the initial edges.5 From a histopathologic perspective, keloids include a random organization of Type I and Type III collagen fibers, whereas hypertrophic scars have an organized parallel pattern of Type III collagen.6,7 Keloids progress to form thick, firm scars that rarely heal spontaneously, unlike hypertrophic scars that can heal unaided over years.5 Since keloids can be distressing to patients, there has been great interest in understanding the key aspects of keloid pathogenesis.

KELOID PATHOPHYSIOLOGY

Keloid formation is theorized to be the result of an imbalance of increased synthesis of collagen and ECM and decreased degradation of these products. Increased synthesis of ECM collagen is thought to be related to the overactivation of keloid fibroblasts via the overexpression of inflammatory mediators—namely, TGF-β1.1 Differential production of isoforms of TGF-β is proposed to be responsible for the excessive collagen production by fibroblasts seen in pathologic scarring.6 Overexpression of TGF-β1 and TGF-β2 with decreased expression of TGF-β3 production results in increased fibroblast activity and ECM collagen formation.1,6,8 Keloid fibroblasts are increasingly sensitive to the effects of TGF-β1 due to the receptor’s upregulation.9 In the process of collagen remodeling, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are key mediators that increase degradation and decrease degradation of ECM, respectively.8 TGF-β1 has been shown to increase TIMP and decrease MMP production, resulting in reduced collagen degradation.10 Other inflammatory proteins such as VEGF and PDGF have been thought to contribute to the overproduction of collagen as well.11,12 The activity of these molecules increasing fibroblast activation might be the result of activating mechano-transduction pathways, stimulated by mechanical stress at certain areas of the body, such as the sternum, shoulder, and suprapubic areas.13–15 Although discovering the cellular processes that mediate keloid formation is still an active area of research, there are a wide variety of therapies that physicians can use to limit keloid formation, progression, recurrence, and symptoms.

PREVENTION AND TREATMENT OPTIONS FOR KELOID MANAGEMENT

Occlusive dressings. Silicone gel sheeting (SGS) is a commonly used occlusive dressing applied to reduce the risk of excessive scar formation. SGS is composed of a semi-occlusive silicone gel sheet combined with a durable silicone membrane.16 Though the prominent mechanism of action of these dressings is unclear, SGS is theorized to act via hydration and occlusion of the wound bed. Scar tissue has been shown to be more prone to transepidermal water loss, possibly reflecting decreased water barrier function of the stratum corneum.17 The SGS creates a moisture-retaining environment that prevents dehydration of the stratum corneum, which, in a downstream manner, limits activation of fibroblasts and subsequent collagen production.18 Several studies have shown that SGS can reduce the incidence of hypertrophic scarring and reduce scar volume.19–23 The use of SGS requires high levels of patient adherence since protocols often require patients to wear the SGS upwards of 12 hours per day for at least 12 months.24,25 Efficacy of SGS has primarily been demonstrated when the dressing is used as a preventative measure rather than a method of treatment.26 The necessary continuous application of SGS in hotter climates might induce a level of humidity that facilitates the formation of bacterial abscesses.27

Compressive therapy. Compression therapy is primarily used as an adjunct to surgical excision to prevent recurrence of ear keloids.28 The mechanisms of pressure therapy are thought to include mechanoreceptor-induced apoptosis of cells in the ECM and/or pressure-induced ischemia that alters fibroblast activity and promotes collagen degradation.6,29 Compression treatments are wide-ranging, including elastic wrap bandages, custom pressure ear molds, earrings, and magnets.6,30,31 Studies have shown that ear keloids treated with compression therapy postexcision have a nonrecurrence rate of 70.5 to 95 percent.32,33 Similar to occlusive dressing therapy, compression therapy has the best results if the pressure device is affixed for at least 12 hours per day for at least six months at a pressure of at least 24mmHg.32–34 If the pressure exceeds 30mmHg, the compression can potentially cause tissue necrosis.31,35

Intralesional steroids. As an accessible and efficacious keloid therapy, intralesional steroids continue to serve as a first-line treatment for many physicians. Typically, triamcinolone is injected at a concentration of either 2.5mg to 20mg for facial keloids or 20mg to 40mg for non-facial keloids.24 Corticosteroids act by suppressing wound inflammation mediators and fibroblast growth while increasing collagen degradation.6,36–38 Mechanisms by which triamcinolone alters fibroblast growth include inducing fibroblast hypoactivity by decreasing TGF-β expression and reducing fibroblast density by increasing fibroblast apoptosis.36,37,39,40 Intralesional triamcinolone as a monotherapy has been shown to reduce keloid recurrence to an average of 50 percent after surgical excision and to reduce scar volume.41–44 However, the therapeutic response rate of intralesional steroid therapy is highly variable.41,45 Potential side effects of corticosteroid injection include pain with injection, skin atrophy, alteration in skin pigmentation, and the formation of telangiectasias.25,45

Topical imiquimod. Used successfully for the treatment of basal cell carcinoma and human papillomavirus-related warts, imiquimod 5% cream has shown promise as an adjuvant therapy for keloids after excision.46 Imiquimod is a Toll-like receptor 7 agonist that limits fibroblast production of collagen via increasing local concentrations of interferon alpha (IFN-α).6,47 IFN-α has been shown to decrease fibroblast activity in a dose-dependent manner, reduce glycosaminoglycan production, and increase collagenase levels.48,49 The reported recurrence rates of excised keloids with daily topical imiquimod 5% cream have ranged from 0 to 88.9 percent with a follow-up time of 20 to 24 weeks.47,50–56 The variability of the keloid recurrence rates with imiquimod therapy is likely related to skin tension at the operative site, with ear keloids having lower recurrence rates than shoulder, chest, and back keloids.57,58 Common side effects of imiquimod include hyperpigmentation, erythema, irritation, and secondary infections that typically resolve upon suspending therapy.6,47,52

Topical mitomycin C. Shown to reduce scarring after ophthalmologic, tracheal, and laryngeal surgery, mitomycin C can reduce keloid recurrence postexcision.59–62 Mitomycin C is an anti-neoplastic derivative of Streptomyces caespitosus that alkylates and cross-links DNA, inhibiting cell proliferation.63 Mitomycin C has been shown in in-vitro studies of adult dermal fibroblasts to decrease fibroblast proliferation at concentrations of 0.4mg/mL and 0.1mg/mL.63,64 In-vitro studies with mitomycin C demonstrated complete cell death with continuous exposure for one week and cellular growth at three weeks after a single exposure of five minutes.63,64 Clinical treatment regimens in the literature include application of an absorbent material soaked in 1mg/mL of mitomycin C for 3 to 5 minutes with reapplication at three weeks.57 Studies that used mitomycin C as the only adjunctive therapy to surgical excision report recurrence rates from 0 to 33 percent at six months, though some studies have demonstrated several patients with nonrecurrence at greater than 12 months.65–71 Intralesional mitomycin C has been shown to result in wound ulceration.66 Reported side effects for mitomycin C have included hypopigmentation and posttreatment pain.66,67

Intralesional and topical 5-fluorouracil (5-FU). Primarily used as a chemotherapeutic, 5-FU is a pyrimidine analog that irreversibly inhibits thymidine synthase, leading to the disruption of DNA replication and cellular proliferation.72 5-FU has been shown in-vitro to reduce fibroblast growth, induce fibroblast apoptosis, and decrease TGF-β-driven collagen synthesis.73,74 When used as a monotherapy for keloids, 5-FU has been reported to have a 21 to 35 percent rate of recurrence at a minimum of three months and maintain keloid volume reduction of keloids for at least six months after the last therapy session in 58 to 65 percent of patients.28,75–77 Studies have described the successful use of 5-FU as therapy for keloid scars resistant to at least one alternate therapy, with a 19 to 47 percent rate of recurrence after at least six months and resolution of painful and itching scar symptoms.28,78–80 Specifically for ear keloids postexcision, one study reported 96 percent of female patients had at least a 75-percent scar volume reduction and 3.57 percent rate of recurrence.28,81 Keloids older than two years might have greater resistance to 5-FU treatment.75,80 Several studies have consistently noted side effects of pain on injection, wound ulceration, and hyperpigmentation after intralesional 5-FU therapy.28,75–77,80 Known systemic side effects of 5-FU include anemia, leukopenia, and thrombocytopenia, though none have been observed after intralesional injection.25 Though topical 5-FU has been used in many dermatologic conditions, no studies have examined the use of topical 5-FU for keloids and hypertrophic scars.82 However, there has been initial successes in patient satisfaction and keloid symptomatology with the use of 5-FU tattooing.83 The process of 5-FU tattooing involves dripping of a 50-mg/mL 5-FU solution onto the keloid, followed by multiple keloid punctures with a 27-gauge needle, and finally dripping of 5-FU solution over the keloid again.83

Interferons. Interferons compose a group of cytokines that mediate complex cellular interactions, including immunoregulatory, antifibrotic, and antiproliferative functions.84,85 Interferon alpha-2b and interferon gamma have been evaluated as therapeutic treatment options for keloids. Both interferon alpha-2b and interferon gamma have been shown to suppress collagen synthesis and scar contraction by fibroblasts, although the extent to which interferon action alters TGF-β–induced fibrosis is unclear.39,48,85–88 There is limited evidence regarding the efficacy of either interferon alpha-2b or interferon gamma compared to placebo. Interferon alpha-2b has been described to be injected at least twice into keloids at dosages of 500,000 to 6 million units.48,89–92 Though one study reported 18.7 percent keloid recurrence after keloid excision with postoperative interferon at a mean follow-up of 7.9 months, several studies reported either no significant difference in recurrence rates or a significant difference in scar volume compared to placebo.89–92 There is no consistent regimen of interferon-alpha-2b that was used among published studies. Similarly, studies evaluating interferon gamma treatment of keloids postexcision did not have consistent treatment regimens. Evaluators injected either 0.1mg or 0.01mg at a frequency of 1 to 3 times per week for 3 to 10 weeks.93–95 Though interferon gamma did consistently demonstrate keloid volume reduction during the treatment period for multiple studies, there is no reliable data for keloid recurrence with this intervention.93–95 Systemic side effects—namely, influenzalike symptoms of fever and myalgias—were noted in several studies using either form of interferon.89,91,95,96 Acetaminophen was used with success as prophylaxis for these systemic symptoms.90,92,94,95

Bleomycin. Bleomycin is an glycopeptide isolate of Streptomyces verticillus that has been predominately used as a chemotherapeutic and secondarily studied as a treatment for keloids and hypertrophic scars.97 As a chemotherapeutic, bleomycin acts to cleave single-stranded and double-stranded DNA and induce apoptosis.98,99 Regarding keloid pathology, bleomycin has been shown to suppress collagen synthesis by dermal fibroblasts, increase collagen turnover, and decrease the levels of lysyl-oxidase required for collagen maturation.100–102 There are multiple methods by which the effectiveness of bleomycin to reduce keloid burden has been studied, including tattooing, dermojet intralesional injection, and intralesional injection plus or minus in combination with electroporation therapy. The bleomycin tattooing protocol has been described as first dripping a bleomycin solution onto the area, then puncturing the treated area multiple times using a 22- to 25-gauge needle.103–105 The evidence to support the efficacy of bleomycin tattooing is difficult to interpret due to the variability of the bleomycin tattooing protocols studied in the current literature. Studies dripped 1.5IU/mL of bleomycin concentrations of 3IU/cm² and 6IU/cm² on patient scars followed by 40 punctures per 1cm² or 5cm².103–105 In the literature, bleomycin tattooing protocols required the administration of multiple sessions, though each study administered each tattooing session at inconsistent time intervals and recorded follow-up at different periods posttreatment.103–105 Still, bleomycin tattooing for keloids has shown some success across each tattooing protocol, with 66 to 77 percent of patients experiencing greater than 70-percent scar flattening.103–105 Recurrence rates after using bleomycin tattooing range from 14 to 28.6 percent at between 10 to 18 months posttreatment.103–105 Saray et al106 studied the use of bleomycin intralesional injections to treat steroid-resistant keloids at 0.6IU/cm² using a dermojet device (MadaJet XL; Mada Inc., Carlstadt, New Jersey).106 This group administered treatment at intervals of four weeks until favorable aesthetic results and symptom reduction were achieved.106 This group reported that 73 percent of patients achieved complete flattening with zero-percent recurrence after at least 16 months, with patients receiving an average of 3.8 sessions per keloid.106 As a novel alternative treatment regimen for increased drug penetration, Manca et al107 treated keloids with intralesional bleomycin injections augmented by electroporation therapy. Electroporation therapy utilizes a current across the keloid area to increase cellular permeability.107 More than half of patients who underwent bleomycin injection therapy were treated with between two and four sessions until adequate improvement was noted.107 Manca et al reported that 94 percent of patients demonstrated a greater than 50-percent reduction and 83 percent of patients had reduction in erythema, pain, and pruritus at 12 months posttreatment.107 Regardless of the method of bleomycin delivery, common side effects included hyperpigmentation, pain on injection, and dermal atrophy.103–107 Saray et al106 helped patients reduce the side effect of hyperpigmentation with the application of topical tretinoin.

Surgical techniques. Beyond simple surgical excision, surgical management of keloids encompasses multiple novel reconstructive techniques that have demonstrated reduced rates of recurrence with treatment-resistant keloids. Simple full or shave excision of a keloid is rarely used as a monotherapy, since recurrence rates for surgical excision range from 45 to 100 percent.6,108 One suggested cause of high recurrence rates with excision has been incomplete surgical margins.109,110 There are several key principles regarding management of the resultant wound bed that are commonly accepted to reduce keloid recurrence. General recommendations for primary wound closure following complete excision include gentle handling of tissue, avoidance of wound bed tension, eversion of wound edges, meticulous approximation of wound edges, and adequate control of infection and bleeding.6,108,111 For ear keloid skin reconstruction, bilayered banner transposition flaps and double-crossed skin flaps have been described to reduce wound bed tension.112,113 As an alternative to primary closure after complete keloid excision, the use of full-thickness skin grafts have been shown to be effective in the literature. Ziccardi et al114 described the use of a full-thickness skin graft from the excised keloid skin with no recurrence at six months.In larger study, Burm et al115 studied the use of full-thickness skin grafts for helical rim keloids defects with exposed cartilage. The skin grafts were placed after the wound bed was de-epithelized 2 to 3mm beyond the original keloid border.115 Burm et al reported no recurrence with no adjunctive therapy for all patients with a follow-up period varying from nine months to six years.115 All of the patients treated by this group had failed prior excision and/or steroid therapy.115 In comparison, Nguyen et al116 described the use of a bilaminar dermal skin replacement system (Integra; Integra LifeSciences Corp., Plainsboro, New Jersey) to create a neodermis with subsequent epidermal skin grafting for treatment-resistant keloids.Without further adjunctive therapy, all of the patients receiving this therapy reported no recurrence at a mean follow-up of 38 to 60 months.116 For large treatment-resistant keloids, pedicle perforator and free-flap coverage of wound defects have been reported with no recurrence at a minimum of 18 months with the use of adjunctive radiation therapy.117–119

In an effort to preserve local viable keloid skin, Lee et al120 first described the core excision procedure. During core excision, the inner fibrous core of the keloid is removed and the resultant defect replaced with a keloid rind flap composed of epidermis and thin dermis. Lee et al demonstrated histological evidence of the subcapsular plexus supplying blood to the keloid rind flaps.120 This technique is supported by data suggesting that fibroblasts at the core of the keloid have lower rates of apoptosis relative to a normal rate of fibroblast apoptosis in the keloid rind flap.121,122 The initial study of keloid core excision reported that 17 percent of patients showed recurrence, with 29 percent of patients suffering from either flap necrosis or congestion.120 Subsequent studies in the literature have reported a recurrence rate of 0 to 44 percent without adjuvant therapy at 18 months.108,122,123

Cryotherapy. Cryotherapy involves the administration of freezing therapy to keloids to reduce scar volume and recurrence. During cryotherapy, the temperature of the keloid scar is lowered below -22°C.124 Low temperatures have been suggested to induce vascular damage, resulting in cell anoxia, cryonecrosis, and coagulative necrosis.124,125 Histologic studies after cryotherapy have highlighted several significant changes in scar tissue structure. Posttreatment scar biopsies have demonstrated the reorganization of collagen fibers into a more compact parallel fashion comparable to classic scar and resultant dermal collagen structure.124–126 Additionally, keloid tissue exposed to cryotherapy has been reported to have reduced myofibroblasts, reduced mast cells, and reduced production of TGF-β by dermal fibroblasts.126,127 Currently, options for cryotherapy include spray, contact, and intralesional therapy. Compared to spray and contact cryotherapy, intralesional cryotherapy facilitates greater freezing of the abnormal keloid and often requires fewer treatment sessions for a satisfactory scar outcome.124,128–130 Intralesional cryotherapy is performed by introducing a needle with or without a cryoprobe into the long axis of the keloid scar, which allows for the passage of liquid nitrogen vapor to freeze the tissue.131 Studies have reported that intralesional cryotherapy can reduce keloid volume by an average of 51.4 to 67.4 percent at 12 months after the last treatment.124,125,132–134 There is some evidence to suggest greater efficacy of intralesional cryotherapy in individuals with keloids of less than 10cm² or with ear keloids.128,132 Regarding patients who failed prior steroid therapy, Gupta et al129 reported 58 percent of their patients had greater than 75 percent flattening at least seven months after the last treatment.129 Recurrence rates from 0 to 24 percent have been reported 6 to 18 months posttreatment.124,125,133,134 Common side effects from intralesional cryotherapy include temporary lesion blistering, mild-to-moderate postoperative pain, and temporary hypopigmentation.124,125,130–134 Some studies have noted that patients with Fitzpatrick skin Types IV to VI have a greater rate of persistent hypopigmentation.133,134

Radiation therapy. Since the beginning of the 20th century, investigators have evaluated different radiation methods to identify the best protocols to treat keloids.135 Primarily, radiation therapy has been shown to be most effective as an adjunctive therapy to surgical excision compared to monotherapy.136,137 Though the mechanism of action of radiation therapy is not known, in-vitro studies of radiation therapy have demonstrated increased rates of premature cellular senescence of keloidal fibroblasts and decreased proliferation in a dose-dependent fashion.138 Currently, there are two primary forms of radiation for keloids: external and internal. X-ray and electron-beam radiation therapy (EBRT) are the two forms of external-beam radiation that have been studied in the literature. Interstitial brachytherapy is a form of internal radiation that uses a hollow catheter placed into the dermis of the keloid scar to deliver localized radiation therapy.139,140 Interstitial brachytherapy can be administered as a low dose rate (LDR) or high dose rate (HDR).140 HDR brachytherapy has been heavily studied in comparison with LDR brachytherapy since LDR treatment time ranges from 20 to 72 hours relative to 5 to 10 minutes for HDR treatment.141,142 Additionally, HDR therapy has been shown to provide better relief of keloid symptoms, such as pain or pruritus, compared to LDR therapy.143 Radiation therapy can be administered in a single treatment dose or fractionated over a period of time. Fractionation of radiation therapy has been shown to reduce posttreatment skin changes compared to single dose therapy.144

The comparison of studies examining radiation therapy is difficult, considering most studies are retrospective reviews that examine variable radiation dosages, variable definitions of recurrence, and variable timing of radiation delivery.145–147 Moreover, retrospective studies on radiation treatment examine mixed populations of hypertrophic scars and keloids and have variable histologic confirmation of keloid pathology.146 Thus, recurrence rates reported in the literature range from 2 to 72 percent.145–148 Still, shared aspects of effective radiation therapy have been supported. Evidence in the current literature suggests the use of different radiation dosages and fractionation protocols depending on the location of the keloid on the body.148–150 Regarding the fractionation of radiation therapy, protocols that use higher-dose fractions for shorter treatment schedules have similar efficacy to longer treatment schedules.149

Recent studies reporting recurrence rates of different keloid radiation methods have compared the biological effective dose (BED) of different protocols. The BED accounts for the radiation dose per fraction, number of fractions, and overall treatment time in a calculation for the relative biological effectiveness of different radiation therapies.150 In a meta-analysis of literature published from 1942 to 2014, Mankowski et al137 used BED calculations to report recurrence rates of 23 percent, 23 percent, and 15 percent for X-ray, ERBT, and brachytherapy protocols, respectively, at an average minimum follow-up of 14.4 months.137 However, this meta-analysis did not exclude studies on the basis of a lack of histological confirmation of keloids and the definition of recurrence was not standardized. A literature review conducted by van Leeuwen et al. only included studies with excisional biopsy verification of keloid pathology and reported mean recurrence rates of 10.5 and 22.2 percent, respectively, for HDR and external radiation therapy.140 Though numerous studies have been conducted for radiation treatment of keloids, there is still no consensus regarding overall dosage and fractionation. Any effort made toward reaching this consensus protocol will be difficult since the comparison of varying protocols using BED calculations is still unreliable. Several studies using BED calculations have differed in the α/β ratio used in the equation.137,149–151 The α/β is a ratio representing an indirect reflection of how the tissue reacts to radiation, with acutely reacting tissues having higher values than late reacting tissues.150 Future studies evaluating radiation therapy must be more rigorous in excluding nonkeloid scars, propose a standardized definition of recurrence, and use a common α/β ratio for BED comparison. In addition to reporting more accurate long-term recurrence rates, short and long-term side effects of radiation therapy must be stringently recorded.

Patients subjected to radiation therapy are at risk for several skin-related complications. In the short term, patients might experience erythema, desquamation, and transient changes in pigmentation.137,152 In the long term, patients might experience permanent dyspigmentation, depigmentation, atrophy, telangiectasias, subcutaneous fibrosis, chronic wounds, and possibly a radiation-induced malignancy.152,153 Risks of skin complications after radiation therapy have been noted to increase with dosage.145,148 Carcinogenesis is considered a long-term risk of radiation therapy for keloids. In a computerized review of literature published from 1901 to 2009, Ogawa et al152 found five cases of keloid-related and hypertrophic scar-related carcinogenesis, where the majority of cancers were related to radiation of surrounding tissue. Of note, in this review, two case reports described patients less than 12 years of age and two patients had received radiation of postburn hypertrophic scars, which are no longer candidates for radiation therapy.152 The risk of carcinogenesis with current radiation therapies, which provide increased precision and smaller margins of treatment, is unclear, as the latency time is greater than 25 years.154 To reduce the risk of carcinogenesis after keloid radiation therapy, surrounding tissues should be adequately shielded (including radiosensitive breast and thyroid tissue), efforts should be made to identify overall carcinogenic patient risk factors, and radiation therapy should be used with caution in young children.148,152

Pulsed-dye laser (PDL). PDL is a form of nonablative laser therapy that targets keloid microvasculature to improve scar appearance. The PDL was initially engineered to treat vascular lesions by adjusting the wavelength of the laser to 585nm to 600nm and specifically targeting hemoglobin and oxyhemoglobin as chromophores.155 With respect to keloid pathology, PDL is thought to cause microvascular damage that results in local hypoxia and decreased nutrient supply, which serves as a catalyst for several biochemical changes within the scar.156–158 Many theories, including the disruption of collagen disulfide bonds and increased levels of collagenase, have been suggested but have yet to be proven.159 Studies have been done on PDL-treated keloid biopsies to elucidate how the laser alters keloid structure. Kuo et al. have reported decreased levels of TGF-β expression, decreased fibroblast proliferation, and increased fibroblast apoptosis from keloid biopsies post-PDL treatment.160–162 This supported the histological evidence of a reduction in the fibroblast and the production of loose, less coarse collagen fibers from keloid biopsies treated with PDL.163

To achieve a therapeutic effect, PDL therapy is typically administered in adjacent nonoverlapping laser pulses over the length of the scar using a laser wavelength of 585nm to 595nm.128,158,163–168 PDL therapy is offered up to 12 to 18 sessions with 4 to 8 weeks between sessions.155,158,169,170 Variables can be adjusted for PDL therapy, including fluence (J/cm²), pulse duration (ms), and spot size (mm).168 Manuskiatti et al170 reported that a shorter pulse width of 0.45ms provided greater sternotomy scar reduction relative to 40ms. The effect of fluence on PDL therapy scar outcomes is still uncertain. Using a split-scar study, Manuskiatti et al165 evaluated several different PDL fluences without noting any significant difference in treatment outcomes, but described faster treatment responses with lower fluences. In contrast, lower fluences (3J/cm²) have also been demonstrated to increase TGF-β levels and collagen synthesis, while higher fluences (10–18J/cm2) have invoked decreases in TGF-β level.171,172

In the current literature, there exists a paucity of studies specifically examining the effect of PDL on keloids. Most studies involve a mixed cohort of patients with either hypertrophic or keloid scars, used subjective evaluation of the scars to assess the effect of PDL therapy, and had a follow-up time of between one and six months after the last treatment.155,164,170 Regarding hypertrophic and keloid scars, Cannarozzo et al155 reported 49 percent of patients had at least a 75-percent improvement in overall scar color, height, pliability, and texture after 4 to 6 sessions.155 Similarly, Al-Mohamady et al164 described a 55-percent improvement in Vancouver Scar Scale after six treatments, with less improvement seen in older scars. Studies evaluating objective measures have shown PDL therapy to reduce scar volume by 24 to 45 percent after 3 to 6 treatment sessions.165,170 Additionally, Alster et al163 demonstrated that PDL therapy relieved keloid symptoms of pain, pruritus, and burning. There is no current data to determine how PDL therapy influences the recurrence of keloid scars, though there is evidence that PDL therapy, in some cases, can cause scar recurrence.168,173

Common side effects of PDL therapy for scars include temporary purpura, blistering, crusting, and postinflammatory pigmentary changes.155,164,165,170 Side effects are more common in individuals with darker skin tones.174 Epidermal cooling with PDL treatment has been shown to be a useful adjunct treatment to reduce adverse complications, including purpura, dyspigmentation, and additional scarring.170,175

Ablative laser. Though ablative carbon dioxide (CO₂) and erbium doped yttrium aluminium garnet (Er: YAG) lasers have been commonly used for scar revision, there is limited evidence regarding the use of these lasers for keloids. CO₂ and Er:YAG lasers target water molecules to cause local tissue changes, including collagen remodeling, increased levels of basic fibroblast growth factor, and decreased levels of TGF-β. CO₂ and Er:YAG lasers can be used to either superficially ablate keloid tissue or surgically excise keloid scars.176–178

There is evidence that multiple ablative CO₂ treatments are necessary for longer-lasting scar improvement. Multiple ablative fractional CO₂ laser treatments have been shown to primarily reduce hypertrophic and keloid scar pliability.176 Similarly, multiple ablative high-energy CO₂ laser treatments with varying laser frequencies have improved keloid pigmentation, pliability, and scar bulk at six months after the last treatment.178 Scrimali et al described monthly fractional CO₂ treatments resulting in no recurrence of keloid and hypertrophic scars at one year after 6 to 12 treatments.179,180 In contrast, Ang et al181 noted complete earlobe keloid recurrence after a single ablative CO₂ treatment.

Compared to simple scalpel surgical excision of keloids, CO₂ laser excision without adjunctive therapy has similarly high rates of recurrence, ranging from 74 to 100 percent at one year, but decreased blood loss and postoperative pain.182,183 Adjunctive intralesional steroid therapy and cyanoacrylate glue have been shown to improve scar revision results of CO₂ laser keloid excision.184,185

There is a paucity of studies evaluating the effects of ablative Er:YAG laser therapy on keloids. Wagner et al186 conducted a pilot study using Er:YAG laser therapy to treat a mixed-patient cohort with hypertrophic and keloid scars. Er:YAG laser therapy was able to reduce scar redness, scar elevation, and scar hardness on average by 50 percent.186

Side effects of laser therapy of keloids have been infrequently reported in studies but include erythema, edema, and hyperpigmentation.178 Hypertrophic scarring, notably on the neck, has been described as a possible side effect to ablative CO₂ resurfacing.187

Laser-assisted drug delivery (LADD). To increase the bioavailability of topical scar therapies, lasers have been used to increase drug penetration beyond the stratum corneum.188,189 In LADD, common ablative lasers, such as CO₂ and Er:YAG lasers, are applied to create cylindrically shaped microablation zones into the skin that allow for topical agents to reach the dermis.190 Though common topical keloid-treating agents, including corticosteroids, 5-FU, and imiquimod have been studied using LADD, there is limited literature investigating the use of LADD for keloid treatment.190,191

Cavalie et al192 studied the use of Er:YAG laser every other week with the twice daily application of topical betamethasone cream until an adequate improvement in keloids was observed. After a median of nine treatments, there was a median overall improvement of 50 percent, with greater improvement seen in acne-induced keloids.192 After final treatment, 22 percent of patients had recurrence within the first two months.192 Subsequently, Park et al193 compared the efficacy of Er:YAG LADD of intralesional triamcinolone acetonide therapy and topical desoxymethasone. This group conducted a split scar study to compare these two therapies and administered each LADD steroid treatment in a total of four sessions with six-week intervals.193 The group noted significant improvement of the scar halves 12 weeks following the last therapy, though there was some worsening noted at the end of the observation period.193 Patients rated their satisfaction with their treatment outcome as “moderately satisfied”at the end of the trial.193

5-FU and imiquimod with LADD have been shown to increase drug penetration and decrease the required dosage for optimal efficacy in murine and porcine skin models.194–196 Further studies are necessary to explore the effectiveness of these topical therapies with LADD for keloid treatment.

Platelet-rich plasma (PRP). PRP is concentrated autologous plasma that contains supra-physiologic levels of platelets and alpha granules with growth factors and cytokines, such as vascular endothelial growth factor, platelet-derived growth factor, and TGF-β.197 PRP has been popularized as an adjunctive treatment to help with a variety of dermatologic conditions, including chronic wounds, alopecia, and scars.198 Recent studies have focused on the role of PRP in altering keloid pathology. In-vivo studies with dermal fibroblasts have demonstrated that PRP increased fibroblast proliferation, expression of collagen, and matrix protein synthesis.199,200 Increased levels of TGF-β in PRP have been proposed to activate a negative feedback mechanism in the TGF-β signaling pathway.201 Currently, PRP has been studied as a postsurgical excision therapy that is injected into the wound bed. Hersant et al202 reported 29 percent keloid recurrence at two years when PRP was used intraoperatively during surgical excision and postoperatively in a monthly regimen for three months.202 This study suggests the potential of PRP to modify abnormal healing of keloid wounds typically seen after only surgical excision. Jones et al203 reported that the use of PRP as an adjunct to surgical excision and X-ray radiotherapy for ear keloids reduces the recurrence rate to six percent at two years.203 Azzam et al204 reported a recurrence rate of 32 percent when PRP was used as an adjunct to surgical excision and cryotherapy.204

CONCLUSION

The breadth of therapies available for the prevention and treatment of keloids is continually expanding, with encouraging recent progress from novel strategies. As clinicians become more familiar with the use of the different injectable treatments and devices described in the literature, reliable data can be gathered regarding their consistent use. Currently, there exist no standardized guidelines for keloid management endorsed by a governing academic body. The present absence of large, high-quality studies evaluating the efficacy different keloid modalities restricts the establishment of standardized guidelines for keloid management. The desire for higher levels of evidence to guide keloid management for all physicians is echoed in the current literature as well as by our study population.25,205–208. Currently, there are no high-quality randomized controlled trials (RCTs) and few low-quality RCTs evaluating different keloid treatments.177,207 Retrospective cohort, prospective cohort, and systematic reviews compose the current evidence for the majority of keloid therapies.6,25,177,207 Durani and Bayat207 noted that poor methodological quality was a common reason that decreased the level of evidence provided by several nonrandomized comparative studies. Designing reliable studies to investigate keloid treatments requires a standardization of experimental methods not currently seen in the literature. There is no consistency among current studies to exclusively study keloids instead of mixed hypertrophic and keloid scar populations or to have consistent means by which to evaluate therapy success. When evaluating keloid therapies, studies should consistently use validated tools for scar assessment, such as the Vancouver Scar Scale and the Patient and Observer Scar Assessment Scale.177 Additionally, studies should make an effort to include subjective measures of reduction in scar volume. A consistent experimental design is necessary to perform comparative studies between treatment modalities. Keloids continue to be a challenging pathology for clinicians, and future treatment regimens must be based on high-quality studies with replicable improvement in outcomes.