Keloid and Hypertrophic Scar 

Updated: Jun 12, 2018
Author: Brian Berman, MD, PhD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Keloids are the result of an overgrowth of dense fibrous tissue that usually develops after healing of a skin injury. The tissue extends beyond the borders of the original wound, does not usually regress spontaneously, and tends to recur after excision. The first description of keloids (recorded on papyrus) concerned surgical techniques used in Egypt in 1700 BCE. Subsequently, 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. Note the image below.

Clawlike outline of a keloid. Courtesy of Dirk M. Clawlike outline of a keloid. Courtesy of Dirk M. Elston, MD.

In contrast, hypertrophic scars are characterized by erythematous, pruritic, raised fibrous lesions that typically do not expand beyond the boundaries of the initial injury and may undergo partial spontaneous resolution. Hypertrophic scars are common after thermal injuries and other injuries that involve the deep dermis.

See 5 Body Modifications and Piercing: Dermatologic Risks and Adverse Reactions, a Critical Images slideshow, to help recognize various body modifications and the related potential complications.

Related articles include Laser Treatment of Scars and Stria Distensae, Keloids, and Widened and Hypertrophic Scar Healing.

Pathophysiology

Hypertrophic scars and keloids can be described as variations of typical wound healing. In a typical wound, anabolic and catabolic processes achieve equilibrium approximately 6-8 weeks after the original injury. At this stage, the strength of the wound is approximately 30-40% that of healthy skin. As the scar matures, the tensile strength of the scar improves as a result of progressive cross-linking of collagen fibers. At this point, the scar is usually hyperemic and it may be thickened, but it tends to subside gradually over months until a flat, white, pliable, possibly stretched, mature scar has developed. When an imbalance occurs between the anabolic and catabolic phases of the healing process, more collagen is produced than is degraded, and the scar grows in all directions. The scar is elevated above the skin and remains hyperemic. Excessive fibrous tissue is classified as either a keloid or a hypertrophic scar.

Kischer and Brody declared the collagen nodule to be the identifying structural unit of hypertrophic scars and keloids.[1] The nodule, which is absent from mature scars, contains a high density of fibroblasts and unidirectional collagen fibrils in a highly organized and distinct orientation. In addition, keloids and hypertrophic scars differ from healthy skin by a rich vasculature, high mesenchymal cell density, and thickened epidermal cell layer. Attempts to clinically differentiate keloids from hypertrophic scars have proved to be difficult in the early phases of formation. Clinical differences become more apparent as lesions mature. The most consistent histologic difference is the presence of broad, dull, pink bundles of collagen (hyalinized bundles of collagen) in keloids, which are not present in hypertrophic scars.

Epidemiology

Frequency

Only humans are affected by keloids, and both dominant and recessive modes of inheritance have been described. Although keloids occur in all age groups, they are rarely found in newborns or elderly persons and have the highest incidence in individuals aged 10-20 years.

Race

Keloids form more frequently in Polynesian and Chinese persons than in Indian and Malaysian persons. As many as 16% of people in a random sampling of black Africans reported having keloids. White persons are least commonly affected.

Sex

The prevalence has been reported to be higher in young females than in young males, probably reflecting the greater frequency of earlobe piercing among females. Keloids and hypertrophic scars affect both sexes equally in other age groups.

Age

Onset occurs most commonly in individuals aged 10-30 years. Keloids occur less frequently at the extremes of age, although an increasing number of presternal keloids have resulted from coronary artery bypass operations and other similar procedures now undertaken in persons in older age groups.

Prognosis

Keloids rarely resolve spontaneously; however, with treatment, they may become softer, less tender, less painful, and less pruritic. Following excision treatment alone, keloids frequently recur (>50%).

Keloids and hypertrophic scars located at most sites are primarily of cosmetic concern; however, some keloids or hypertrophic scars can cause contractures, which may result in loss of function if overlying a joint or in significant disfigurement if located on the face.

Keloids and hypertrophic scars are associated genetically with HLA-B14, HLA-B21, HLA-Bw16, HLA-Bw35, HLA-DR5, HLA-DQw3, and blood group A.

Patient Education

Advise patients to avoid local skin trauma (eg, skin piercing, tattoos) and to control inflammatory acne. Initially, focus is placed on the alleviation of symptoms.

 

Presentation

History

Keloids and hypertrophic scars do not usually cause symptoms, but they may be tender, painful, or pruritic or they may cause a burning sensation. In addition to symptomatic relief, cosmetic concern is the primary reason patients seek medical intervention.

Physical Examination

Origins of lesions

Keloids manifest as exaggerated growths of scar tissue, usually in areas of previous trauma. Keloids extend past the areas of trauma, projecting above the level of the surrounding skin, but they rarely extend into underlying subcutaneous tissue.

Hypertrophic scars remain limited to the traumatized area and regress spontaneously within 12-24 months, although regression may not necessarily be complete.

Clinical findings in lesions

Keloids range in consistency from soft and doughy to rubbery and hard. Studies have demonstrated how to differentiate and classify keloids according to how they feel. Early lesions are often erythematous. Lesions become brownish red and then pale as they age. Lesions are usually devoid of hair follicles and other functioning adnexal glands. Note the images below.

Keloid. Courtesy of Dirk M. Elston, MD. Keloid. Courtesy of Dirk M. Elston, MD.
Keloid. Courtesy of Dirk M. Elston, MD. Keloid. Courtesy of Dirk M. Elston, MD.
Keloid. Courtesy of Dirk M. Elston, MD. Keloid. Courtesy of Dirk M. Elston, MD.

Once lesions occur, the clinical course varies. Most lesions continue to grow for weeks to months and others grow for years. Growth is usually slow, but keloids occasionally enlarge rapidly, tripling in size within months. Once they stop growing, keloids do not usually cause symptoms and remain stable or involute slightly.

Keloids on the ears, neck, and abdomen tend to be pedunculated. Keloids on the central chest and extremities are usually raised with a flat surface, and the base is often wider than the top.

Most keloids are round, oval, or oblong with regular margins; however, some have clawlike configurations with irregular borders. Keloids overlying a joint can contract and restrict movement.

Most patients present with 1 or 2 keloids; however, a few patients, especially patients with spontaneous keloids, have multiple lesions, as do patients who develop keloids as a consequence of acne or chickenpox.

Keloids may be distinguished from hypertrophic scars by their clawlike projections, which are absent in the hypertrophic scar.

Frequency of lesion sites

In white persons, keloids tend to be present, in decreasing order of frequency, on the face (with cheek and earlobes predominating), upper extremities, chest, presternal area, neck, back, lower extremities, breasts, and abdomen.

In black persons, the descending order of frequency tends to be earlobes, face, neck, lower extremities, breasts, chest, back, and abdomen.

In Asian persons, the descending order of frequency is earlobes, upper extremities, neck, breasts, and chest.

Causes

The increased prevalence of keloids paralleling increased cutaneous pigmentation suggests a genetic basis or, at least, a genetic linkage. Trauma to the skin, both physical (eg, earlobe piercing, surgery) and pathological (eg, acne, chickenpox), is the primary cause identified for the development of keloids. The presence of foreign material, infection, hematoma, or increased skin tension can also lead to keloid or hypertrophic scar formation in susceptible individuals. Transforming growth factor-beta and adiponectin are implicated in the pathogenesis.[2]

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Diagnosis is usually based on clinical findings. Biopsy may confirm the diagnosis in equivocal cases.

Other Tests

There is no objective method or reliable device to measure and assess the physical properties of keloids and hypertrophic scars, and they have generally been assessed subjectively using the Vancouver burn scar scale. A novel device, the Vesmeter, was recently studied by Niyaz et al for the quantification of the physical properties of keloids and hypertrophic scars.[3] Simultaneous automatic assessment of 6 physical properties were made (ie, skin elasticity, viscosity, viscoelastic ratio, penetration depth, relaxation time, hardness) is performed while the sensor is in contact with the lesion. Data are transmitted to a personal digital assistant (electronic handheld information device) via Bluetooth.

The most important advantages demonstrated of the Vesmeter were its ability to measure the physical properties of keloids and hypertrophic scars at any point during the clinical course and digitalize the data and its capability to evaluate clinical improvement or deterioration after a given treatment. Vesmeter was demonstrated to be sensitive and can detect very slight changes in skin hardness and elasticity.

Histologic Findings

Formation of collagen in keloids and hypertrophic scars in the inflammatory stage takes much longer than usual in healing wounds. Collagen fibers in granulation tissue are arranged in a whorled pattern. In keloids, the nodules demonstrate thick, hyalinized bands in the central portion of the nodule. Note the images below.

Histology of keloid demonstrating central zone of Histology of keloid demonstrating central zone of hyalinized collagen (hematoxylin and eosin stain). Courtesy of Dirk M. Elston, MD.
Histology of keloid demonstrating thick hyalinized Histology of keloid demonstrating thick hyalinized collagen bundles (hematoxylin and eosin stain). Courtesy of Dirk M. Elston, MD.
 

Treatment

Medical Care

No single therapeutic modality is best for all keloids. The location, size, and depth of the lesion; the age of the patient; and the past response to treatment determine the type of therapy used.

Prevention is key, but therapeutic treatment of hypertrophic scars and keloids includes occlusive dressings, compression therapy, intralesional corticosteroid injections, cryosurgery, excision, radiation therapy, laser therapy, interferon (IFN) therapy, 5-fluorouracil (5-FU), doxorubicin, bleomycin, verapamil, retinoic acid, imiquimod 5% cream, tamoxifen, tacrolimus, botulinum toxin, hydrogel scaffold, and over-the-counter treatments (eg, onion extract; combination of hydrocortisone, silicon, and vitamin E).

Other promising therapies include antiangiogenic factors, including vascular endothelial growth factor (VEGF) inhibitors (eg, bevacizumab), phototherapy (photodynamic therapy [PDT], UVA-1 therapy, narrowband UVB therapy), transforming growth factor (TGF)–beta inhibitors, tumor necrosis factor (TNF)–alpha inhibitors (etanercept), recombinant human epidermal growth factor (rhEGF), and recombinant human interleukin (rhIL)–10, which are directed at decreasing collagen synthesis.

Prevention

Prevention is the first rule in keloid therapy. Avoid performing nonessential cosmetic surgery in patients known to form keloids; however, the risk is lower among patients who have only earlobe lesions. Close all surgical wounds with minimal tension. Incisions should not cross joint spaces. Avoid making midchest incisions, and ensure that incisions follow skin creases whenever possible.

Standard Treatments

These include occlusive dressings, compression therapy, and intralesional corticosteroid injections.

Occlusive dressings

Occlusive dressings include silicone gel sheets and dressings, nonsilicone occlusive sheets, and Cordran tape. These measures have been used with varied success, and overall the quality of the studies has been suboptimal.[4] Antikeloidal effects appear to result from a combination of occlusion and hydration, rather than from an effect of the silicone.

Previous studies have shown that in patients treated with silicone occlusive sheeting with pressure worn 24 h/d for up to 12 months, 34% showed excellent improvement, 37.5% showed moderate improvement, and 28% demonstrated no or slight improvement.

Of patients treated with semipermeable, semiocclusive, nonsilicone-based dressings for 8 weeks, 60% experienced flattening of keloids, 71% had reduced pain, 78% had reduced tenderness, 80% had reduced pruritus, 87.5% had reduced erythema, and 90% were satisfied with the treatment.

Cordran tape is a clear surgical tape that contains flurandrenolide, a steroid that is uniformly distributed on each square centimeter of the tape, and it has been shown to soften and flatten keloids over time.

Compression therapy

Compression therapy involves pressure, which has long been known to have thinning effects on skin. Reduction in the cohesiveness of collagen fibers in pressure-treated hypertrophic scars has been demonstrated by electron microscopy.

Cellular mechanoreceptors may have an important role of compression therapy. Mechanoreceptors induce apoptosis and are involved in the integrity of the extracellular matrix. An increase in extracellular matrix rigidity produced by compression garments leads to a higher level of mechanoreceptor activity and therefore more cellular apoptosis. Migration, proliferation, and differentiation of cells has been shown to be affected by rigidity; therefore, the rigidity caused by compression may also inhibit the differentiation and proliferation of scar fibroblasts in vivo.[5, 6]

Compression treatments include button compression, pressure earrings, ACE bandages, elastic adhesive bandages, compression wraps, spandex or elastane (Lycra) bandages, and support bandages. In one study, button compression (2 buttons sandwiching the earlobe applied after keloid excision) prevented recurrence during 8 months to 4 years of follow-up observation.

Other pressure devices include pressure earrings and pressure-gradient garments made of lightweight porous Dacron, spandex (also known as elastane), bobbinet fabric (usually worn 12-24 h/d), and zinc oxide adhesive plaster. Overall, 60% of patients treated with these devices showed 75-100% improvement.

Corticosteroids

Corticosteroids, specifically intralesional corticosteroid injections, have been the mainstay of treatment. Corticosteroids reduce excessive scarring by reducing collagen synthesis, altering glucosaminoglycan synthesis, and reducing production of inflammatory mediators and fibroblast proliferation during wound healing. The most commonly used corticosteroid is triamcinolone acetonide (TAC) in concentrations of 10-40 mg/mL administered intralesionally with a 25- to 27-gauge needle at 4- to 6-week intervals.

Intralesional steroid therapy as a single modality and as an adjunct to excision has been shown to be efficacious in various studies. Response rates varied from 50-100%, with recurrence rates of 9-50% in completely resolved scars. When combined with excision, postoperative intralesional TAC injections yielded a recurrence rate of 0-100%, with most studies citing a rate of less than 50%. Complications of repeated corticosteroid injections include atrophy, telangiectasia formation, and pigmentary alteration.

A standardized corticosteroid therapy protocol has been shown to reduce the recurrence of keloids and hypertrophic scars after excision. Intralesional TAC injection was performed after removal of the sutures and then once every 2 weeks (total of 5 treatments). In addition, patients were instructed to apply corticosteroid ointment twice daily for 6 months to the wounds after suture removal. Only 3 (14.3%) of 21 keloids and 1 (16.7%) of 6 hypertrophic scars recurred.[7]

Aradi et al studied 21 earlobe keloids that were treated using keloidectomy with core fillet flap and given intraoperative intralesional steroid injections. This study showed an efficacy of 87.6%. Immediate recurrence was 9.5%, with an average of 29.9 months of follow up and with few complications encountered. Subjectively, 82.3% of patients were satisfied.[8]

Published data show molecular-based evidence of the clinical benefits of adding 5-fluorouracil to a steroid injection for improved scar regression and reduced recurrence of keloids. 5-Fluorouracil–induced G2 cell-cycle arrest and apoptosis may be associated with p53 activation and p21 up-regulation. 5-Fluorouracil significantly affects the treatment when combined with triamcinolone, leading to more significant cell proliferation inhibition, apoptosis, Col-1 suppression, and MMP-2 induction.[9]

Current and New Treatments

Current treatments for keloids and hypertrophic scars include intralesional IFN; 5-FU; doxorubicin; bleomycin; verapamil; retinoic acid; imiquimod 5% cream; tacrolimus; tamoxifen; botulinum toxin; TGF-beta3; rhIL-10; VEGF inhibitors; etanercept; mannose-6-phosphate inhibitors (M6P); onion extract; the combination of hydrocortisone, silicon, and vitamin E; PDT; intense pulsed light (IPL); UVA-1; combination butyrate and docosahexaenoic acid[10] ; and narrowband UVB.

IFN therapy, including IFN alfa, IFN beta, and IFN gamma, has been demonstrated in in vitro studies to reduce keloidal fibroblast production of collagen types I, III, and VI mRNA.

IFN alfa and IFN beta also reduce fibroblast production of glycosaminoglycans (GAGs), which form the scaffolding for the deposition of dermal collagen. IFN gamma enhances GAG production.

IFN alfa, IFN beta, and IFN gamma have been shown to increase collagenase activity. Studies have shown that IFN gamma modulates a p53 apoptotic pathway by inducing apoptosis-related genes. p53 is a protein synthesized following DNA damage. Once damage is repaired, p53 is degraded. Mutations of this protein are believed to predispose cells to hyperproliferation, possibly resulting in keloid formation. In addition, p53 is a potent suppressor of interleukin (IL)–6, a cytokine implicated in hyperproliferative and fibrotic conditions.

IFN injected into the suture line of keloid excision sites may be prophylactic for reducing recurrences. Berman and Flores reported statistically significant fewer keloid recurrences in a study of 124 keloid lesions after postoperative IFN alfa-2b injection treatment (5 million U, 1 million U injected per cm of scar) into keloid excision sites (18%) versus excision alone (51.1%) and TAC treatment (58.4%).[11]

Tredget et al showed a significant increase in the rate of scar improvement compared with the control period of time (P = .004) after injecting 9 patients with hypertrophic scars with 1 X 106 units of human recombinant IFN alfa-2b subcutaneously, daily for 7 days, and then 2 X 106 units administered 3 times per week for 24 weeks in total.[12] Scar assessment (P< .05) and scar volume (P< .05) also improved after 3 months of treatment. No recurrences were reported after stopping IFN therapy.

Conejo-Mir et al reported that 66% of keloids (n = 20) did not recur after 3 years of follow-up after treating 30 keloids with ultrapulse carbon dioxide laser ablation followed by sublesional and perilesional injections of 3 million IU of IFN alfa-2b 3 times per week.[13]

In a 2008 prospective study, Lee et al reported decreases in depth (81.6%, P = .005) and volume (86.6%, P = .002) treating 20 keloids with a combination of intralesional TAC and IFN alfa-2b compared with only a nonsignificant improvement (P = .281 and P = .245, respectively) obtained in 20 keloids treated with TAC alone.[14]

Notably, however, several studies have failed to demonstrate the efficacy of IFN alfa-2b for the treatment of keloids and hypertrophic scars, including a case series of 5 patients treated by Wong et al,[15] a case series by al-Khawajah of 22 patients with keloids using lower doses of IFN alfa-2b than in prior studies,[16] and a prospective randomized clinical trial by Davison et al in which 50 patients with keloids received intraoperative intradermal injections of IFN alfa-2b at 10 million U/mL or TAC at 40 mg/mL, both receiving an extra injection 1 week later.[17]

Hypertrophic scar intralesional injections of human recombinant IFN gamma at 200 mcg (6 X 106 U) per injection for 4 weeks have been reported by Pittet et al to be effective for relieving the symptoms in 6 of 7 patients and decreases in redness, swelling, firmness, and lesion area in 7 of 7 patients.[18] At week 16, the reappearance of symptoms was minimal in only 2 of 7 patients and a small increase in the lesion area occurred in 4 of 7 patients, although these lesions remained smaller than the original area.

5-Fluorouracil

5-FU, a pyrimidine analogue with antimetabolite activity, inhibits fibroblastic proliferation in tissue culture and is believed to reduce postoperative scarring by decreasing fibroblast proliferation. Its efficacy and safety have been reported when used as a monotherapy or when used in combination with other drugs (eg TAC) for the treatment of other fibrosing conditions, including infantile digital fibromatosis, knuckle pads, rheumatoid nodules, and adverse foreign body reaction and sarcoidal granulomatous complications after soft tissue filler injection. Some data suggest that 5-FU is effective in the treatment of hypertrophic scars and is somewhat effective in small keloids. Several studies have shown the effectiveness of 5-FU.

In a retrospective study of 1000 patients with hypertrophic scars and keloids over a 9-year period, the most effective regimen was found to be 0.1 mL of TAC (10 mg/mL) and 0.9 mL of 5-FU (50 mg/mL) up to 3 times a week.

A total of 85% of keloids showed more than 50% improvement in an open study by Kontochristopoulos et al in which 20 keloids were treated once weekly with intralesional 5-FU (50 mg/mL) for an average of 7 treatments, with a recurrence rate of 47% within 1 year of the treatment. The Ki-67 proliferative index was significantly reduced (P = .0001) after treatment.[19]

Nanda and Reddy treated 28 patients with multiple keloids in a prospective, randomized, uncontrolled clinical trial with weekly intralesional injections of 5-FU at 50 mg/mL and reported almost 80% of the patients showing more than 50% improvement. Regression from the periphery and flattening occurred in all patients. In 22 of 28 patients, the symptoms completely disappeared, while the rest showed a good response. Decrease in size was reported in 70% of the patients.[20]

5-FU in combination with other therapies significantly increases the efficacy over single modalities.

In a double-blind randomized study, 40 patients with keloids or hypertrophic scars received 8 weekly intralesional injections of TAC 10 mg/mL or a combination of TAC 4 mg/mL plus 5-FU 45 mg/mL. At week 12, both groups showed improvement; however, the lesions in the TAC plus 5-FU group had significantly greater pliability and less erythema, height, length, and width (P< .05) than the TAC group compared with baseline (P<.05).<ref>21</ref>

In a randomized clinical trial by Asilian et al, 69 patients with keloids and hypertrophic scars were treated with a combination of 5-FU (50 mg/mL), TAC (40 mg/mL), and a 585-nm flashlamp-pumped pulsed-dye laser (PDL) at 5-7.5 J/cm2, showing that it was more effective than the TAC and TAC plus 5-FU.[22] At week 12, a statistically significant reduction in length, height, and width was observed in all groups compared with baseline (P< .05). In a randomized clinical trial, Manuskiatti and Fitzpatrick found a statistically significant clinical improvement in keloidal and hypertrophic sternotomy scars using these 3 modalities separately and a combination of TAC and 5-FU compared with baseline. No difference was found between the 4 treatment modalities.[23]

5-FU was used to treat a patient with keloids and hypertrophic scars post facial dermabrasion. The patient received 6 intralesional injections of 5-FU with silicone sheets applied afterwards over a 3-month span. During 7 months of follow up, a significant improvement in the size, color, and texture of the scars was noticed. In addition, the pain and itching had fully resolved.[24]

Sadeghinia et al compared the use of intralesional TAC 40 mg/mL at 20 mg/cm2 of lesion and 5-FU (50 mg/ml) tattooing in a double blind study. Forty patients were randomized into 2 groups, which received the treatment every 4 weeks for 12 weeks. At week 44, both groups showed improvement in all parameters (erythema, pruritus, height, surface, and induration), but improvement was more significant in the 5-FU group (P< .05).[25]

Although some studies have shown good results, it appears triamcinolone is a better-tolerated and less toxic alternative to 5-FU in the management of keloids.[26]

Doxorubicin (Adriamycin)

Doxorubicin (Adriamycin) is a commonly used chemotherapeutic agent that irreversibly inactivates prolyl 4-hydroxylase in human skin fibroblasts and has been shown to inhibit collagen alpha-chain assembly.

Sasaki et al showed through sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis that doxorubicin, at a clinically therapeutic concentration of 12.5 µm, inhibits the assembly of collagen triple-helical molecules.[27] SDS-PAGE analysis of control cultures showed a large fraction of [3H]proline-labeled procollagen polypeptides in triple-helical conformation; however, after the addition of doxorubicin at 12.5 µm, a very small amount of intact alpha-chains were found. These results suggest that the impaired wound healing observed in cancer patients who receive doxorubicin may result from the inhibition of prolyl 4-hydroxylase.

Another mechanism of doxorubicin-induced inhibition of collagen synthesis includes the inhibition of the enzyme prolidase, which is key in the process of collagen resynthesis, cleaving imidodipeptides containing C-terminal, and making proline available for its recycling and further generation of new collagen. Muszynska et al demonstrated this process in cultured human skin fibroblasts, also suggesting that this inhibition is a posttranslational event.[28, 29]

Other agents such as doxycycline, other nonsteroidal anti-inflammatory drugs (ie, acetylsalicylic acid, sodium salicylate, phenylbutazone, indomethacin), daunorubicin, gentamicin, netilmicin, anthracycline)[30] are also capable of inhibiting prolidase in cultured human skin fibroblasts. Further studies are warranted to determine if doxorubicin or any of the above-mentioned agents can be useful to treat patients with excessive scarring.

Bleomycin

Bleomycin injections cause necrosis of keratinocytes with a mixed inflammatory infiltrate. Several studies have demonstrated that bleomycin can be used effectively to treat keloids and hypertrophic scars.

Bleomycin was given at a concentration of 1.5 IU/mL to 13 patients using the multiple-puncture method. Bleomycin was dripped onto the lesion, and then multiple punctures were made on the lesions using a syringe. Seven patients had complete flattening, 5 patients had highly significant flattening, and 1 patient had significant flattening. Likewise, Espana et al also reported complete flattening in 6 of 13 patients, highly significant flattening in 6 of 13 patients, and significant flattening in a single patient. Two patients presented a recurrence as a small nodule 10 and 12 months after the last infiltration.[31]

In another study of 31 keloids, patients were treated with 3-5 infiltrates of bleomycin within a 1-month period. Total regression occurred in 84% of the keloids, and both keloid volume and functional impairment were reduced.

Bodokh and Brun reported complete flattening in 69.4% of 36 patients with keloids and hypertrophic scars.[32] Saray et al obtained complete flattening in 73.3%, highly significant flattening in 6.7%, and moderate flattening in 6.7% of lesions after the administration of jet intralesional injections of bleomycin in 15 patients.[33]

In the only randomized clinical trial using the tattooing technique, with which smaller amounts of the drug are absorbed, thus minimizing systemic adverse effects, Naeini et al reported significantly better results with intralesional bleomycin compared with the control group (ie, combination of cryotherapy and TAC) in lesions larger than 100 mm2 (P = .03).[34] Local complications, such as hyperpigmentation, were observed in 75% of the patients.

Fifty patients with keloids and hypertrophic scars were treated with intralesional bleomycin. Three applications were given at 15-day intervals, and a fourth and final application was given 2 months after the third application. Complete flattening was observed in 44%, significant flattening in 22%, adequate flattening in 14%, and no flattening in 20%. Pruritus was relieved completely in 89% of patients.[35]

Manca et al have found that electroporation in combination with bleomycin is an effective treatment for keloids or hypertrophic scars or for those who are nonresponders to other treatments. In their study, 20 patients with keloids or hypertrophic scars had a median reduction of 87% in volume and 94% of the lesions showed volume reduction of more than 50%. Scar pliability and erythema scores were also significantly reduced. Less pruritus was observed in 89% of patients and pain was reduced in 94%.[36]

The combination of bleomycin and intralesional steroids such as triamcinolone has repeatedly shown good results. More recently, Camacho-Martinez et al designed a two-part study. They used 0.375 IU of bleomycin and 4 mg of triamcinolone acetonide to 1 cm2 and it was considered an acceptable procedure for the treatment of keloids. The best results were obtained in keloids larger than 1 cm2 or when divided into 1-cm2 square areas.[37]

Verapamil

Verapamil is a calcium channel blocker that blocks the synthesis and secretion of extracellular matrix molecules (eg, collagen, GAGs, fibronectin) and increases fibrinase.

In a study of 22 patients with keloids, patients were treated with surgical excision in combination with reconstruction with W-plasty or skin grafting and injection of verapamil (5 treatments of verapamil at 2.5 mg/mL-varying doses from 0.5-5 mL), depending on keloid size) over a 2-month period and were evaluated at 2-year follow-up. Two patients had keloids that decreased in size from the original lesion, 2 patients had hypertrophic scars, 4 patients had pruritus, and 1 patient had a keloid on the donor site (skin grafting site). The case series reported an average of 6.4 in patient satisfaction on a scale from 1 to 10.[38]

D’Andrea et al, from a case-control comparative study, reported resolution in 54% of the patients who had their keloids treated by a combination of surgical excision, silicon sheeting, and intralesional verapamil versus 18% in the control group without intralesional verapamil.[39] The recurrence rate was 36% in the active group after 18 months of follow up.

In a case series, Skaria reported complete resolution of 4 of 6 keloids and 1 of 2 hypertrophic scars at 1-year follow-up after surgical removal of the scar and further intralesional injection of verapamil at doses of 2.5 mg/mL.[40]

Lawrence reported 55% cured earlobe keloids in 52% of the patients after the combination of surgical excision, intralesional verapamil, and pressure earrings after an average of 28 months of follow-up.[41]

In a randomized clinical trial, Margaret Shanthi et al compared intralesional verapamil and intralesional TAC for the treatment of keloids and hypertrophic scars, reporting a reduction in vascularity, pliability, height, and width in both groups after 3 weeks of treatment. This result was maintained at 1 year after stopping the treatment. Although the rate of improvement was faster in the TAC group, overall, no difference was noted between the 2 groups.[42]

Ahuja et al studied 40 patients (48 scars) and compare the effects of triamcinolone and verapamil injections. This group concluded that even though the criterion standard first-line treatment is still triamcinolone, verapamil is almost equally effective, with very few adverse effects, and offers a therapeutic option to treat larger and recalcitrant scars.[43]

Retinoic acid

Retinoic acid decreases normal tonofilament and keratohyalin synthesis, increases the production of mucoid substances and the epidermal cell growth rate, and inhibits DNA synthesis in vitro.

In a clinical trial involving 21 patients with 28 keloids and hypertrophic scars, topical retinoic acid was applied for at least 3 months twice daily and showed favorable results in 77-79% of the lesions. This includes a decrease in the size and symptoms of the scar.[44]

In addition, because retinoids affect collagen metabolism, another study involving 9 females and 2 males with keloids treated with 0.05% tretinoin topically for 12 weeks showed a significant decrease in weight (P< .04) and size (P< .01) of the keloids when comparing the status of the lesions at the beginning of the study and at week 12.[45]

In vitro studies have demonstrated that retinoids can modulate collagen production and the proliferation of normal and keloidal fibroblasts. In vivo applications of 0.05% topical retinoic acid can lead to a reduction of hypertrophic scars in 50-100% of patients and of keloids in less than 20% of patients. The most common adverse effects reported have been photosensitivity, irritant contact dermatitis, and skin atrophy.

Retinoids can be used also as a preventive treatment. Kwon et al compared silicone gel and tretinoin cream use after studying 44 scars post surgery. They found that after 24 weeks of treatment, both therapeutic modalities were equally effective in preventing hypertrophic scars and keloids compared with the control group.[46]

Imiquimod

Imiquimod (1-[2-methylpropyl]-1H-imidazo[4,5-c]quinolin-4-amin) belongs to the family of imidazoquinolines. Imiquimod induces TNF-alpha, IFN-alpha and IFN-gamma, IL-1, IL-4, IL-5, IL-6, IL-8, and IL-12 and alters the expression of markers for apoptosis.

In one study, 13 keloids were treated with excision in combination with nightly applications of imiquimod 5% cream for 8 weeks. Ten patients with 11 keloids completed the 6-month study, and no keloids recurred after 6 months. Mild irritation was experienced with the application of imiquimod, and some patients needed a vacation period from the medication. Hyperpigmentation was experienced by more than half of the patients in the study.[47]

In 2 different pilot studies, imiquimod 5% cream was applied on postshaved or totally excised earlobe keloids. It was demonstrated that the recurrence rate on postshaved keloids was 0% after 12 months of follow-up and 75% recurrence-free after 24 weeks of parallel keloid excision. Although the presence of local adverse events did not affect the treatment, a resting period was needed.[48, 49]

In a different study, 15 patients with hypertrophic scars 2 months after breast surgery were treated with either petrolatum or imiquimod 5% cream. At 24 weeks, almost all the scars treated with imiquimod scored better after assessment with standardized scales. The results demonstrated that imiquimod treatment improved scar quality and color match after surgery.[50]

More recently, in study by Chuangsuwanich et al, 45 patients with excised keloids were treated with imiquimod 5% cream 2 weeks after the operation, on alternate nights, for 8 weeks.[51] After a follow-up period of 6-9 months, 10 of the keloids recurred (28.6% overall recurrence rate), with adverse effects found in 13 patients (37.1%). Interestingly, the keloids localized on the pinna had the lowest recurrence rate (2.9%) compared with those at the chest wall or neck (83.3% and 14.3%, respectively).

Tacrolimus

Tacrolimus is an immunomodulator that inhibits TNF-alpha. Gli -1, an oncogene, has been found to be overexpressed in fibroblasts of keloids. Inhibition of this oncogene may restore the natural apoptosis process and decrease proliferation of the ECM protein.[52] Rapamycin, a close analogue of tacrolimus, was used in an in vitro study and was found to inhibit the gli -1 oncogene, thus giving a rationale to initiate clinical trials of topical tacrolimus and rapamycin.

In an open-label pilot study, 11 patients used tacrolimus 0.1% ointment twice daily for 12 weeks on their keloids. Although the results were not statistically significant, the study showed a decrease in induration, tenderness, erythema, and pruritus for most patients.[53]

Kim et al observed the resolution of a keloid in a patient during a course of topical tacrolimus for atopic dermatitis.[52]

Sirolimus

Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR), a serine/threonine kinase that regulates collagen expression. By inhibiting mTOR, sirolimus blocks the response to IL-2 and decreases ECM deposition.[54] Similar to rapamycin, sirolimus inhibits Gli -1 signal transduction. mTOR kinases form 2 distinct multiprotein complexes, mTORC1 and mTORC2. In an in vitro and ex vivo study, 2 compounds, KU-0063794 and KU-0068650, were demonstrated to be potent and highly selective competitive inhibitors of mTORC1 and mTORC2 compared with rapamycin, which inhibits mTORC1 alone. The compounds have shown promising antifibrotic activity, with apparent no toxicity in vivo.[55]

A higher concentration of VEGF and higher blood vessel density has been found in the basal layer of the epidermis of keloidal tissue in comparison to normal skin. In co-cultured keloid keratinocytes and fibroblasts exposed to sirolimus, VEGF expression has shown to be down-regulated in a dose-dependent manner. Through inhibition of VEGF, sirolimus may control the expression profile of underlying dermal fibroblasts.

Tamoxifen

Tamoxifen, a synthetic nonsteroidal antiestrogen used to treat breast cancer, has been shown to inhibit proliferation of keloid fibroblasts and their collagen synthesis in monolayer cultures. Hu et al demonstrated that tamoxifen exhibits a dose-dependent and reversible inhibition of contraction of adult human dermal fibroblast in vitro.[56]

Tamoxifen has also been shown to reduce TGF-alpha, and its isoform TGF-alpha1, production by keloid fibroblasts in vitro. Mikulec et al have shown that keloid fibroblasts have significantly lower TGF-alpha1 production when exposed to 16 µmol/L of tamoxifen at day 2 of culture when compared with control keloid fibroblasts (P = .05).[57]

Botulinum toxin A

Botulinum toxin A (BTA) is a neurotoxin that causes a flaccid paralysis of the local musculature and reduces skin tension. This reduction in the skin tensile force during the course of wound healing may represent a novel therapeutic target for treating keloids.

In an in vitro study, 64% of cultured fibroblasts were found to be in the G0-G1 phase of the cell cycle when exposed to BTA, while 35.4% were in the proliferative phases (ie, G2, M, S). In comparison, cultured fibroblasts that were not exposed to BTA had the following distribution: 36% (G0-G1) and 64% (proliferative phases).[58] The effect of BTA on the cell cycle distribution of fibroblasts may indicate that BTA can improve the eventual appearance of and inhibit the growth of hypertrophic scars and keloids.

In a prospective, uncontrolled study evaluating the effects of BTA in the treatment of keloids, 12 keloids were injected intralesionally at a concentration of 35 U/mL, with the total dose varying from 70-140 U per session. Injections were given at 3-month intervals for a maximum of 9 months. At 1-year of follow up, the therapeutic outcomes were excellent (n = 3), good (n = 5), and fair (n = 4), with no patients failing therapy or showing signs of recurrence.[59]

Nineteen patients with hypertrophic scars received intralesional injections of BTA (2.5 U/mL at 1-mo intervals) for 3 months. All patients showed acceptable improvement of the scars at 6 months of follow up. The erythema, pruritus, and pliability scores were significantly lower post-BTA injections compared with baseline.[60]

In a case series, 12 patients (n=10 whites, n=01 Chinese, and n=01 South Asian) with keloids in different parts of the body (n=9 presternal; n=3 neck, thigh, and cheek), previously treated with conventional modalities, received between 20 and 100 units of BTA on each visit over the past 5 years (no frequency specified). Eight patients had concurrent alternating intradermal triamcinolone injections. Complete flattening of the keloids was obtained after a range of 2-43 months of repeated injections. Two of 12 patients had recurrences adjacent to previously treated areas. One patient developed atrophy, leading to ulceration and further recurrence.[61]

Intramuscular injections of BTA along with scar revision techniques on the face may help to reduce the development of a wider scar.[62]

Larger, randomized, controlled studies are warranted to determine the role of BTA in the treatment of keloids and hypertrophic scars.

TGF-beta and isomers

TGF-beta and its isomers have been shown to play a central role in fibrotic disorders characterized by excessive accumulation of interstitial matrix material in the lungs, kidneys, liver, and other organs. TGF-beta1 and TGF-beta2 have been shown to stimulate fibroblasts to produce collagen and have a direct and independent effect on the contraction of fibroblasts in vitro. However, TGF-beta3 may prevent scarring.

A study by Shah et al demonstrated that exogenous addition of TGF-beta3 reduces fibronectin and collagen types I and III deposition in the early stages of cutaneous rat wound healing and in overall wound scarring.[63]

A new antifibrotic product, avotermin (Juvista, Renovo; Manchester, United Kingdom) has been extensively studied. Avotermin is derived from human recombinant TGF-beta3. This product has shown promise in a phase I trial and 2 phase II trials completed in the United Kingdom. In these studies, wounds treated with avotermin showed a statistically significant improvement in scar appearance, with a response rate of greater than 70%. After analyzing safety data on more than 1500 human subjects, avotermin does not seem to have safety or tolerability issues for use in the prevention or reduction of scarring.

In a randomized, double-blind, placebo-controlled, within-patient, phase II trial to investigate the safety and efficacy of 200 ng per 100 μL per linear cm of wound margin of avotermin when administered twice following scar revision surgery, the overall analysis showed that the primary endpoint (ie, photographic evaluation by a lay panel over a period from week 6 to month 7 postsurgery using a visual analogue scale) was met (P = .038). Investigator assessment at 7 months postsurgery using a visual analogue scale also obtained statistical significance (P = .036). Approximately 75% of the 7-month scars assessed from avotermin-treated wounds were considered to have a structure more like normal skin compared with the placebo in the histopathological analysis.[64]

Bush et al evaluated 71 subjects (aged 18-45 y) who received avotermin at 50 or 200 ng/100 μL/linear centimeter of wound margin. Incisional wounds on the inner aspect of each upper arm were randomized to receive the following: no injection (standard wound care only), 1 intradermal injection of avotermin or placebo (immediately before surgery), or 2 injections of avotermin or placebo (immediately before surgery and 24 h later). Avotermin at 200 ng/100 μL/linear centimeter, administered once or twice, achieved significant improvements in scar appearance compared with controls (P< .02 for all comparisons). The 50-ng dose, administered twice, achieved significant improvements in scar appearance versus placebo (P = .043). Treatment was well tolerated.[65]

A double-blind, randomized study (ie, RN1001-0042) evaluated the efficacy and safety of 4 doses of avotermin given once. A total of 156 patients undergoing bilateral surgery to remove varicose leg veins by saphenofemoral ligation and long saphenous vein stripping were studied. Four different doses of avotermin were administered (5, 50, 200 or 500 ng per 100 µL, at 100 µL per linear cm of wound margin). The primary efficacy variable was lay panel Total Scar Score (ToScar) assessed between 6 weeks and 7 months. Avotermin 500 ng significantly improved groin scar appearance compared with placebo (mean lay panel ToScar difference 16·49 mm; P = .036). Avotermin 500 ng per 100 µL per linear cm of wound margin given once is well tolerated and significantly improves scar appearance.[65, 66, 67, 68, 69]

TGF therapy is currently being studied in ongoing clinical trials for use as an adjuvant treatment following excision of earlobe keloids.[70, 71, 72]

Epidermal growth factor

Epidermal growth factor (EGF) is a growth factor produced by platelets, macrophages, and monocytes and is activated by binding with the EGF receptor present on keratinocytes and fibroblasts.[73] It acts by stimulating keratinocyte proliferation and altering fibroblast activity, resulting in reduced healing time and improved tensile strength of scars.[74, 75] It has been found to be involved in wound healing. It is up-regulated early in the fetal period and is thought to be an important cytokine in scarless fetal healing.[76]

The role of recombinant human EGF (rhEGF) in scars is being investigated. In a murine full-thickness wound model, rhEGF decreased TGF-beta1 expression, suppressing collagen deposition and reducing cutaneous scars.[77]

rhEGF has also been studied in human studies. Shin et al evaluated the effects of rhEGF for scar prevention post thyroidectomy. The total Vancouver Scar Scale (VSS) was significantly lower in the treatment compared with the control group, although erythema, pigmentation, elasticity, and hydration were not significantly different.[78]

Hydrogel scaffold

Hydrogel scaffold is approved for used in Europe for improvement of wound healing and scarring and is available as an injectable porcine gelatin-dextran hydrogel scaffold.[79] Its approval is for injection of incisional sites immediately prior to closure. It is thought to function as a lattice for fibroblast adherence, leading to more regulated and organized distribution, with improved wound healing outcome.

Hydrogel scaffold has also been studied in the treatment of keloids. Berman et al studied 19 subjects with 26 ear keloids. They were treated with excision followed by injection with 3 mL of the scaffold per 2.5 cm of wound margin, along with wound margin approximation and closure.[80] At 12-month follow-up, the recurrence rate was 19.2%, and each of the recurrences measured less than 15% of the original volume, with 60% of the recurrences measuring less than 5%. As well, the average patient scar satisfaction on a scale of 1-10 was 9.9.

Other potential targets

Potential therapeutic targets include decapentaplegic homolog (Smad)3, high-mobility group box protein-1, and calcimycin.[113, 114, 115]

Surgical Care

Surgical treatments include cryotherapy, excision, laser therapy, and other light therapies.

Cryotherapy

Cryosurgical media (eg, liquid nitrogen) affects the microvasculature and causes cell damage via intracellular crystals, leading to tissue anoxia. Generally, 1, 2, or 3 freeze-thaw cycles lasting 10-30 seconds each are used for the desired effect. Treatment may need to be repeated every 20-30 days. Cryotherapy can cause pain and permanent depigmentation in selected patients. As a single modality, cryosurgery led to total resolution with no recurrences in 51-74% of patients after 30 months of follow-up observation.

Newer methods of application of liquid nitrogen include the insertion of a lumbar puncture needle through the long axis of the keloid, from one side to the other, passing the liquid nitrogen with an intravenous drip set for 2 freeze-thaw cycles of 20-30 seconds each for 5-10 sessions. Flattening was achieved in 75% of the patients.[81] A single treatment with an intralesional cryoprobe was used to treat 10 earlobe keloids in 10 white patients, obtaining a statistically significant reduction in the scar volume of 67.4% after 18 months of follow up compared with baseline measurements. Zero recurrences were reported. Other scar parameters also improved.[82]

Excision

Apply basic soft tissue handling techniques at primary wound repair sites. Carefully plan the closure with minimal tension, paralleling the relaxed skin tension lines. Use buried sutures, when necessary, for a layered closure and to reduce tension. Whenever feasible, apply pressure dressings and garments during the immediate postoperative period to wounds in patients in whom hypertrophic scars and keloid formation occur.

Decreased recurrence rates have been reported with excision in combination with other postoperative modalities, such as radiotherapy, injected IFN, or corticosteroid therapy. Excisional surgery alone has been shown to yield a 45-100% recurrence rate and should very rarely be used as a solitary modality, although excision in combination with adjunct measures can be curative. Most studies in which excisional surgery was combined with injected steroids reported a recurrence rate of less than 50%. Surgery followed by adjunctive radiotherapy has obtained recurrence rates of 0–8.6%.[83, 84, 85]

The authors have studied the effects of topically applied imiquimod 5% cream (Aldara) on the postexcision recurrence rates of 13 keloids excised surgically from 12 patients.[47, 86] Starting the night of surgery, imiquimod 5% cream was applied for 8 weeks. Patients were examined at weeks 4, 8, 16, and 24 for local erythema, edema, erosions, pigment alteration, and/or recurrence of the keloid. Of the 11 keloids evaluated at 24 weeks, none (0%) recurred. The rate of hyperpigmentation was 63.6%. Two cases of mild irritation and superficial erosion cleared with temporary discontinuation of imiquimod. Both patients completed the 8 weeks of topical therapy and the final 24-week assessment. At 24 weeks, the recurrence rate of excised keloids treated with postoperative imiquimod 5% cream was lower than recurrence rates previously reported in the literature.

Laser Therapy

Ablative lasers

Carbon dioxide, argon laser, and Nd:YAG laser (1064 nm)

Ablation of keloids and hypertrophic scars using a carbon dioxide laser (10,600 nm) can cut and cauterize the lesion, creating a dry surgical environment with relatively minimal tissue trauma. When used as a single modality, the carbon dioxide laser was associated with recurrence rates of 39-92%, and when the carbon dioxide laser was combined with postoperative injected steroids, it was associated with recurrence rates of 25-74%.

A Korean study included 30 patients with hypertrophic scars treated with a combination of 3 different therapeutic modalities: 10600-nm ablative carbon dioxide laser (AFL), copper bromide laser (CBL), and intralesional TAC. At the end of the study, CBL achieved better outcomes for vascularity and pigmentation. AFL and AFL plus TAC were especially effective with regard to thickness and pliability. AFL produced epidermal resurfacing due to collagen remodeling. CBL plus TAC did not aggravate vascularity and pigmentation, suggesting that CBL may compensate for the erythema resulting from TAC. In conclusion, the combination of CBL, AFL, and intralesional TAC may provide a new treatment option for hypertrophic scars.[87]

Erbium:Yttrium aluminum garnet laser(Er:YAG)

Er:YAG laser showed a decrease of 51.3% in redness, 50% in elevation, and 48.9% in hardness of keloids in one study after treating 21 keloids. The recurrence rate was not reported.[88]

Similar to the carbon dioxide laser, the argon 488-nm laser can induce collagen shrinkage via generation of excessive localized heat. The argon laser has demonstrated recurrence rates of 45-93%.

Nonablative lasers

Pulsed-dye laser (585 nm)

The 585-nm PDL provides photothermolysis, resulting in microvascular thrombosis. Beginning in the 1980s, authors noted that scars became less erythematous, more pliable, and less hypertrophic after treatment with the 585-nm PDL. The findings were later confirmed using objective measurements of erythema by reflectance spectrometry readings, scar height, and pliability measurements. Because of its efficacy, safety, and relatively low cost, the PDL remains the laser treatment of choice for hypertrophic scars. Multiple publications have continued to confirm the role of the 585-nm PDL for the treatment of keloids and hypertrophic scars.

In a randomized clinical trial, Manuskiatti et al treated 10 keloidal or hypertrophic median sternotomy scars with a 585-nm flashlamp-pumped PDL at fluences of 3, 5, and 7 J/cm2, and one segment was left untreated as a control.[23] They showed consistently better results in the treatment groups over the control. A trend was obtained towards lower fluences having more rapid onset of benefits and enhanced resolution of erythema, induration, and elevation of the scar. Multiple treatment sessions achieved greater clinical improvement.

Alster treated 44 bilateral, symmetric hypertrophic breast-reduction scars with a 585-nm PDL at 4.5-5.5 J/cm2 alone or in combination with intralesional TAC at 10-20 mg/mL injected immediately after the PDL irradiation.[89] All scars showed clinical improvement. The average pliability scores decreased by 50% after 2 sessions in both groups. The concomitant use of TAC reduced symptom scores by 70% compared with PDL alone (50%).

In a prospective, randomized clinical trial, Nouri et al treated 11 patients with 12 postoperative scars with 585-nm PDL at 3.5 J/cm2 versus no treatment.[90] The average overall improvement scores after one treatment was superior to the control (P = .0002). Vascularity improved 54% in treated halves, compared with 8% in controls. (P = .002). A total of 38% of halves returned to normal vascularity, compared with 0% in controls. Pliability improved 64% versus 1%, respectively (P = .002). A total of 62% of halves returned to normal pliability compared with 0% in control halves. The cosmetic appearance score was significantly better for the treated halves than for the untreated controls (7.3 vs 5.2; P = .016).

In contrast, Wittenberg et al found in a prospective, single-blinded, randomized, controlled study an overall reduction in blood flow (P = .001), volume (P = .02), and pruritus (P = .005) over time after a follow-up period of 4 months after treatment discontinuation, but no differences were noted among treatment and control groups treating hypertrophic scars with a 585-nm flashlamp-pumped PDL at 6.5-8 J/cm2 or silicone gel sheeting, or no treatment.[91]

Pulsed-dye laser (595 nm)

Two studies have demonstrated that the 585-nm PDL has more effectively cleared port-wine stains than the 595-nm PDL at the same settings. Murine studies determined that the beneficial effect of lasers inhibiting the scar tissue growth decreased as the wavelength of the laser was increased from 585 to 600 nm. Further studies are necessary to obtain similar conclusions in human tissue. However, longer wavelength (eg, 595 nm) is an alternative vascular-specific laser for dark-skinned patients, with higher amounts of epidermal melanin, which absorbs more readily the 585-nm wavelength, causing nonspecific damage to pigmented epidermis. Currently, 595-nm PDL systems incorporate in the handpiece a cryogen-spray cooling device, which permits safe and effective treatment of hypertrophic scars by raising the threshold for epidermal damage, avoiding the resultant epidermal necrosis when the skin surface temperatures exceeds 70°C immediately after PDL exposure.

In a prospective randomized clinical trial, Conologue et al treated 16 patients with postoperative scars immediately after suture removal with a 595-nm cryogen-cooled PDL at 8 J/cm2 and showed significant improvement (60%) versus the untreated control (-3%) in the average sum of all clinical parameters measured.[92] Improvement was noted in vascularity (69%) versus the control (0%) (P = .53) and in pliability (67%) compared with the control (-8%) (P = .337).

In order to compare the 0.45-millisecond (short) pulse width with the 40-millisecond (long) pulse width, Manuskiatti et al treated 19 patients with keloidal and hypertrophic sternotomy scars in a prospective randomized clinical trial, with a 595-nm PDL at 7 J/cm2 and a cryogen spray cooling device.[93] The short pulse width demonstrated greater overall improvement (P = .046) and scar pliability. Both pulse widths significantly reduced scar height compared with baseline; however, no differences were found between the groups. No effects were noted on scar erythema with either treatment. Both treatments were safe and effective in dark-skinned individuals.

Bellew et al randomly treated 15 hypertrophic scars with a 595-nm long-pulsed PDL at 7 J/cm2 with a concomitant skin-surface cooling device or with an IPL system with a 570-nm cut-off filter and a fluence of 40-45 J/cm2 and a triple pulse, reporting a mean improvement in the long-pulsed PDL group of 80% compared with 65% in the IPL group.[94] However, no statistical difference was noted between the 2 groups. Both systems are equally effective in improving the appearance of hypertrophic surgical scars. IPL minimizes the risk of purpura.

In contrast, however, Alam et al found no beneficial effect on clinical scar appearance at 6 weeks post treatment versus untreated control, after treating 20 patients with postoperative scars in a prospective, randomized, controlled trial using a 595-nm PDL at 7 J/cm2 and a 30-millisecond dynamic cooling spray.[95]

Neodymium:Yttrium, aluminum, garnet laser (1064 nm) (Nd:YAG)

Several studies, mostly case series, have been published on the Nd:YAG laser (1064 nm). A case series showed persistent flattening of keloids or hypertrophic scars in 5 (22.7%) of 22 scars 12 months after Nd:YAG treatment.[96] A clinical trial obtained a reduction in the size of the scars of 10% or greater in 8 (36.4%) of 22 patients treated with Nd:YAG at 3- to 4-week intervals.[97] The Nd:YAG laser appears to improve the cosmetic appearance of keloids and may be a superior treatment modality than PDL lasers.[98]

Light Therapies

Photodynamic therapy

Chiu et al studied the in vitro effect of 5-aminolevulinic acid (ALA) and 635-nm diode laser irradiation on keratinocyte-fibroblast co-culture (Raft model), determining that 5 J/cm2 reduces tissue contraction and collagen synthesis and preserves fibroblast viability.[99] The authors hypothesized that ALA-PDT may be used as an adjuvant therapy postsurgical excision of keloids.

The clinical evidence for PDT is limited. A case series reported the use of red-light MAL-PDT in 20 patients with keloids divided in 3 groups: (1) existing keloid scars (scar of no more than 2 mm in height), (2) postsurgical debulking (keloid scars of any size reduced/debulked to a keloid scar of at most a height of 2 mm), and (3) post-total surgical excision (of any size scar, which was removed in total). Patients received 3 PDT treatments at weekly intervals with an incubation time of 3 hours. After 9 months of follow up, all but one patient developed recurrence.[100] Other limited case series and case reports using ALA- or MAL-PDT have shown similar promising results.[98]

Ultraviolet A-1

UVA-1 (340-400 nm) has been reported as an effective treatment for morphea and systemic sclerosis through induction of collagenase I (matrix metalloproteinase I) produced by fibroblasts. Asawanonda et al reported clinical improvement in one keloid in addition to the histological reappearance of normal-looking collagen and elastic fibers, while others have not reported as good clinical results.[101]

Animal models have shown a significant decrease in dermal thickness and collagen content in scars irradiated postsurgically with UVA-1 at 110 J/cm2. UVA-1 exposure to hypertropic scars in rabbits after epithelialization may lead to softening of the scar, thinning of the skin, and a decrease in collagen content. However, immediate irradiation with UVA-1 after wounding could not prevent the development of hypertrophic scarring in rabbits.[102]

Two German studies have evaluated the efficacy of UVA-1 irradiation for the treatment of skin conditions with altered dermal matrix, including keloids, scleroderma, scars, granuloma annulare, and acne keloidalis nuchae. The studies are complete, but results are not yet published.[103, 104]

Narrowband UVB

Narrowband UVB in the wavelength range of 310-315 nm (peak at 312 nm) has demonstrated for more than 20 years to be less potent than broadband UVB for erythema induction, hyperplasia, edema, sunburn cell formation, and Langerhans cell depletion from the skin. Studies on human skin fibroblasts by Choi et al have demonstrated that narrowband UVB reduces type I collagen synthesis by down-regulating TGF-beta1 expression at both the mRNA and protein levels and promoting the release of MMP-1.[105] Oiso et al reported flattening of a hypertrophic scar after treating a patient with vitiligo and a Koebner phenomenon with low-dose narrowband UVB (ie, 300 mJ/cm2) once a week for 4 months.[106]

Broadband UVB

Broadband UVB (290-320 nm) at high doses (up to 320 mJ/cm2) has also been theorized to improve fibrosing skin conditions, including keloids, hypertrophic scars, scleroderma, acne keloidalis nuchae, old burn scars, and granuloma annulare, among other related conditions with altered dermal matrix, safely through collagenase-mediated removal of excess dermal collagen via activation of MMP-1 pathways in patients with increased skin pigmentation.[107]

High keloid incidence is found among individuals with high melanin content in their skin. Since melanin serves as a UVB light absorber, lack of UVB light penetration may play a role in keloid etiology. Wirohadidjojo et al evaluated the effect that UVB irradiation to monolayer keloid fibroblasts has on cell proliferation, collagen deposition, and TGF-beta1 production. Keloid fibroblasts were cultures and exposed to various dosages of UVB irradiation. Collagen depositions and TGF-beta1 production were measured. UVB 100 and 150 mJ/cm2 were able to suppress keloid fibroblast viabilities and collagen accumulation significantly (P< .01). Significant suppression of TGF-beta1 production required UVB irradiation of 150 mJ/cm2 (P< .01). UVB irradiation with a minimal dosage of 150 mJ/cm2 is possible therapy for keloid prevention and treatment.[108]

Intense pulsed light

Bellew et al obtained equal effectiveness improving the appearance of hypertrophic surgical scars with IPL compared with 595-nm long-pulsed PDL.[94] IPL minimized the risk of developing postlaser purpura, frequently seen in patients treated with long-pulsed PDL.

Cartier reported that IPL was effective in treating and improving inflamed hypertrophic scars in 3 patients.[109]

Other studies have suggested that IPL is effective for improving the appearance of hypertrophic scars and keloids, regardless of their origin, and in reducing the height, redness, and hardness of scars. Erol et al evaluated hypertrophic scars in 109 patients (including keloids) after treatment using an IPL (Quantum) device, administered at 2- to 4-week intervals, with patients receiving an average of 8 treatments.[110] Overall clinical improvement was seen in the appearance of scars, and reductions in height, erythema, and hardness were seen in the majority of the patients (92.5%). Improvement was excellent in 31.2% of the patients, good in 25.7%, moderate in 34%, and minimal in 9.1%. Patient satisfaction was very high.

Complications

Trauma to the keloid may predispose the lesion to erosion and localized bacterial infection.

Long-Term Monitoring

Because of the high rate of recurrence, a follow-up period of at least 1 year is necessary to fully evaluate the effectiveness of therapy. Close follow-up monitoring is vital during immediate and aggressive treatment of subsequent keloid formation. Noncompliant patients who are lost to follow-up care for months often return for further evaluation long after further adjunct treatment would have been most beneficial.

Preoperative evaluation is critical to assess a patient's motivation for treatment and to assess the patient's ability to participate in long-term care and follow-up visits.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Corticosteroids

Class Summary

These agents have profound and varied metabolic effects. They possess anti-inflammatory and immunosuppressive properties. The most commonly used corticosteroid is triamcinolone acetonide  (TAC).

Triamcinolone (Aristospan, Kenalog-10)

Triamcinolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability. It is approved by US Food and Drug Administration (FDA) for use in keloids.

Immunomodulators

Class Summary

This is a family of glycoproteins produced mainly by eukaryotic cells when induced by viral and nonviral triggers. Antiviral properties include induction of 2'-5' A synthetase, ribonuclease L, and protein kinase P1. Antiproliferative properties include induction of 2'-5' A synthetase, inhibition of growth factors, enhancement of p53, and down-regulation of c-myc, c-fos, and certain c-ras. Immunoregulatory properties include induction of class I and II MHC antigens, increase of natural killer cells, and inhibition of the production of TH-2 cytokines.

Interferon alfa-2b (Intron-A)

This is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Its immunomodulatory effects include suppression of tumor cell proliferation, enhancement of macrophage phagocytic activity, and augmentation of lymphocyte cytotoxicity. It is not approved by the FDA for use in hypertrophic scars and keloids.

Interferon beta 1a (Avonex, Rebif)

This is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Its immunomodulatory effects include suppression of tumor cell proliferation, enhancement of macrophage phagocytic activity, and augmentation of lymphocyte cytotoxicity. It is not approved by the FDA for use in hypertrophic scars and keloids.

Interferon alfa-n3 (Alferon N)

Interferon alfa is a protein product either manufactured from a single-species recombinant DNA process or obtained from pooled units of donated human leukocytes that have been induced by incomplete infection with a murine virus.

The mechanisms by which interferon alfa exerts antiviral activity are not understood clearly. However, modulation of the host immune response may play an important role.

Peginterferon alfa 2b (PEG Intron, PegIntron Redipen, Sylatron)

PEG-IFN consists of IFN alfa-2b attached to a single 12-kd PEG chain. It is excreted by the kidneys. PEG-IFN has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified IFN, which permits more convenient once-weekly dosing and significantly improves quality of life for patients.

Pegylated interferon alfa-2a (Pegasys)

PEG-IFN alfa-2a consists of IFN alfa-2a attached to a 40-kd branched PEG molecule. PEG-IFN has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified IFN, which permits more convenient once-weekly dosing and significantly improves quality of life for patients.

Calcium Channel Blockers

Class Summary

Treatment of keloids and hypertrophic scars with verapamil has shown a reduction in vascularity, pliability, height, and width of the lesions.

Verapamil (Isoptin, Calan, Verelan PM)

Verapamil blocks the synthesis and secretion of extracellular matrix molecules and increases fibrinase. It is not approved by the FDA for use in hypertrophic scars and keloids.

Antineoplastic Agents

Class Summary

These agents inhibit cell growth and proliferation.

Bleomycin

Injections cause necrosis of keratinocytes. It is not approved by the FDA for use in hypertrophic scars and keloids.

Fluorouracil topical (Adrucil)

Fluorouracil is a pyrimidine analog that inhibits fibroblastic proliferation in tissue culture and is believed to reduce postoperative scarring by decreasing fibroblast proliferation. It is not approved by the FDA for use in hypertrophic scars and keloids.

Doxorubicin (Adriamycin)

Doxorubicin irreversibly inactivates prolyl 4-hydroxylase in human skin fibroblasts and inhibits collagen alpha-chain assembly.  It is not approved by the FDA for use in hypertrophic scars and keloids.

Tamoxifen

Tamoxifen competitively binds to estrogen receptors, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects.

Retinoid-like Agents

Class Summary

These agents decrease normal tonofilament and keratohyalin synthesis, increase the production of mucoid substances and the epidermal cell growth rate, and inhibit DNA synthesis in vitro.

Tretinoin topical (Retin-A, Retin-A Micro, Renova)

Although the exact mechanism of action is unknown, retinoids decrease the cohesiveness of abnormal hyperproliferative keratinocytes, modulate keratinocyte differentiation, and have anti-inflammatory properties. It is not approved by the FDA for use in hypertrophic scars and keloids.

Immunosuppressants

Class Summary

These agents inhibit immune processes that promote inflammation.

Tacrolimus ointment (Protopic)

Tacrolimus suppresses release of cytokines from T cells. It also inhibits transcription for genes that encode interleukin 3 (IL-3), IL-4, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor–alpha (TNF-alpha), all of which are involved in the early stages of T-cell activation.

Additionally, tacrolimus may inhibit release of preformed mediators from skin mast cells and basophils and may down-regulate expression of high-affinity IgE receptor (FCeRI) on Langerhans cells. It is not approved by the FDA for use in hypertrophic scars and keloids.

Topical Skin Products

Class Summary

The agent imiquimod has been reported to show some efficacy. However, the mechanism of action of imiquimod cream in treating keratosis is unknown.

Imiquimod (Aldara, Zyclara)

Imiquimod is an immune response modifier currently approved for the treatment of genital and perianal warts. It is capable of inducing IFN-alpha, TNF-alpha, IL-1, IL-6, and IL-8. Studies using 5% cream in mice showed significant induction of IFN-alpha at the application site occurring as early as 2 hours after treatment. At 4 hours after application, increases in IFN-alpha mRNA levels were found, indicating an increase in transcription. It is not approved by the FDA for use in hypertrophic scars and keloids.

 

Questions & Answers

Overview

What are keloids?

What are hypertrophic scars?

What is the pathophysiology of keloids and hypertrophic scars?

What is the role of collagen nodules in the pathophysiology of keloids and hypertrophic scars?

Which age group is at highest risk for keloids and hypertrophic scars?

What are the racial predilections for keloids and hypertrophic scars?

How does the incidence of keloids and hypertrophic scars vary by sex?

What age group is more commonly affected by keloids and hypertrophic scars?

What is the prognosis of keloids and hypertrophic scars?

What are the areas commonly affected by keloids and hypertrophic scars?

Which genes have been associated with keloids and hypertrophic scars?

What information about keloids and hypertrophic scars should patients receive?

Presentation

What are the signs and symptoms of keloids and hypertrophic scars?

How do keloids and hypertrophic scars manifest?

Which physical findings are characteristic of keloids and hypertrophic scars?

What is the clinical progression of keloids and hypertrophic scars develop?

How are keloids characterized?

How are keloids and hypertrophic scars differentiated?

How does the site of keloids and hypertrophic scars vary by race?

What causes keloids and hypertrophic scars?

DDX

What are the differential diagnoses for Keloid and Hypertrophic Scar?

Workup

What is the role of lab studies in the diagnosis of keloids and hypertrophic scars?

How are the physical properties of keloids and hypertrophic scars assessed?

What are the benefits of the Vesmeter in the diagnosis of keloids and hypertrophic scars?

Which histologic findings are characteristic of keloids and hypertrophic scars?

Treatment

What is the basis for treatment selection in patients with keloids?

What are treatment options for keloids and hypertrophic scars?

How are keloids and hypertrophic scars prevented?

What are the standard treatments for keloids and hypertrophic scars?

What are different types of occlusive dressings used for keloids and hypertrophic scars?

How effective are occlusive dressings for keloids and hypertrophic scars?

What is the mechanism of action for compression therapy in the treatment of keloids and hypertrophic scars?

What are the types of compression treatment for keloids and hypertrophic scars?

What is the role of corticosteroids in the treatment of keloids and hypertrophic scars?

How effective are corticosteroids in the treatment of keloids and hypertrophic scars?

How should corticosteroids be administered for treatment of keloids and hypertrophic scars?

What is the role of keloidectomy in the treatment of keloids and hypertrophic scars?

What is the role of 5-fluorouracil in the treatment of keloids and hypertrophic scars?

What is the role of imiquimod in the treatment of keloids and hypertrophic scars?

How are keloids and hypertrophic scars managed?

What is the role of IFN therapy work in the treatment of keloids and hypertrophic scars?

How effective is IFN therapy in treating keloids and hypertrophic scars?

What is the mechanism of action for 5-fluorouracil (5-FU) in the treatment of keloids and hypertrophic scars?

What is the efficacy of 5-fluorouracil (5-FU) for the treatment of keloids and hypertrophic scars?

What is the role of doxorubicin in the treatment of keloids and hypertrophic scars?

What is the role of bleomycin in the treatment of keloids and hypertrophic scars?

How effective is bleomycin for treatment of keloids and hypertrophic scars?

Which bleomycin combination therapies are effective in the treatment of keloids and hypertrophic scars?

What is the role of verapamil in the treatment of keloids and hypertrophic scars?

What is the role of retinoic acid in the treatment of keloids and hypertrophic scars?

What are the pros and cons of using retinoic acid as treatment for keloids and hypertrophic scars?

What is the recurrence rate of keloids and hypertrophic scars following treatment with imiquimod?

What is the role of tacrolimus in the treatment of keloids and hypertrophic scars?

What is the role of sirolimus in the treatment of keloids and hypertrophic scars?

What is the role of tamoxifen in the treatment of keloids and hypertrophic scars?

What is the role of botulinum toxin A (BTA) in the treatment of keloids and hypertrophic scars?

How effective is botulinum toxin A (BTA) in treating keloids and hypertrophic scars?

What is the role of TGF-beta in the treatment of keloids and hypertrophic scars?

How safe and effective is TGF-beta for treatment of keloids and hypertrophic scars?

What is the role of epidermal growth factor (EGF) in the treatment of keloids and hypertrophic scars?

What is the role of hydrogel scaffold, in the treatment of keloids and hypertrophic scars?

What are the potential therapeutic targets in the treatment of keloids and hypertrophic scars?

What are the surgical options for treatment of keloids and hypertrophic scars?

What is the role of cryotherapy in the treatment of keloids and hypertrophic scars?

How is excision performed in the treatment of keloids and hypertrophic scars?

What is the efficacy of excision for treatment of keloids and hypertrophic scars?

What is the role of imiquimod in the postexcision care of keloids and hypertrophic scars?

What is the role of laser therapy in the treatment of keloids and hypertrophic scars?

What is the efficacy of laser therapy for the treatment of keloids and hypertrophic scars?

How effective is the Erbium:Yttrium aluminum garnet laser (Er:YAG) for the treatment of keloids and hypertrophic scars?

What is the role of pulsed-dye laser (PDL) (585 nm) in the treatment of keloids and hypertrophic scars?

How effective is pulsed-dye laser (PDL) (585 nm) for treatment of keloids and hypertrophic scars?

What is the role of pulsed-dye laser (PDL) (595 nm) in the treatment of keloids and hypertrophic scars?

How effective is pulsed-dye laser (PDL) (595 nm) for treatment of keloids and hypertrophic scars?

What is the role of Neodymium:Yttrium, aluminum, garnet laser (1064 nm) (Nd:YAG) in the treatment of keloids and hypertrophic scars?

What is the role of photodynamic therapy (PDT) in the treatment of keloids and hypertrophic scars?

What is the role of Ultraviolet A-1 (UVA-1) in the treatment of keloids and hypertrophic scars?

What is the role of Narrowband UVB in the treatment of keloids and hypertrophic scars?

What is the role of Broadband UVB in the treatment of keloids and hypertrophic scars?

What is the role of intense pulsed light (IPL) in the treatment of keloids and hypertrophic scars?

What are the complications of keloids and hypertrophic scars?

What is included in the long-term monitoring of keloids and hypertrophic scars?

Medications

What is the goal of drug treatment for keloids and hypertrophic scars?

Which medications in the drug class Topical Skin Products are used in the treatment of Keloid and Hypertrophic Scar?

Which medications in the drug class Immunosuppressants are used in the treatment of Keloid and Hypertrophic Scar?

Which medications in the drug class Retinoid-like Agents are used in the treatment of Keloid and Hypertrophic Scar?

Which medications in the drug class Antineoplastic Agents are used in the treatment of Keloid and Hypertrophic Scar?

Which medications in the drug class Calcium Channel Blockers are used in the treatment of Keloid and Hypertrophic Scar?

Which medications in the drug class Immunomodulators are used in the treatment of Keloid and Hypertrophic Scar?

Which medications in the drug class Corticosteroids are used in the treatment of Keloid and Hypertrophic Scar?