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Abnormal wound healing: keloids

David T. Robles, MD, PhD, Daniel Berg, MD*

Division of Dermatology, Department of Medicine, University of Washington Medical Center,

PO Box 356524, Seattle, WA 98105-6920, USA

Abstract Wound healing is a complex and carefully regulated physiologic response to a traumatic injury.Deregulation of this coordinated process can lead to exuberant scar formation as seen in keloids and

hypertrophic scars. Despite their common occurrence, keloids remain one of the most challenging

dermatologic conditions to successfully treat and may have significant psychosocial impact for the

patient. In this review, we discuss the clinical features, genetics, epidemiology, and treatment of keloids.

D 2007 Elsevier Inc. All rights reserved.

Introduction

The formation of a scar can be thought of as a process

that has evolved over millions of years for the purpose of

restoring functionality, not esthetic quality. In some indi-viduals, an aberrant healing process results in excessive scar

formation that may extend well beyond the original

boundaries of the wound, resulting in a significant and

troubling cosmetic defect. These lesions may be symptom-

atic with pruritis, pain, and loss of function and may carry a

significant psychosocial burden. The focus of this review

with regard to abnormal wound healing is the pathogenesis

of keloid formation. Many treatment modalities have been

described; some, as discussed here, have shown some

promise when used in combination with other treatments.

Keloids: clinical features

The term keloid was originally described in the 1800s as

bcheloid,Q which is derived from the Greek root bchele,Q

which means bcrab claw.Q1 A keloid is a benign hyper-

proliferative growth of dense fibrous tissue developing from

an abnormal healing response to a cutaneous injury. By

definition and in distinction from a hypertrophic scar, keloids

extend beyond the borders of the original wound invading

normal skin. They appear as firm nodules, are often pruriticand painful, and generally do not regress spontaneously.

Unlike hypertrophic scars, which typically reach a certain

size and subsequently stabilize or regress, keloids may

continue to grow with time. In a study of 28 patients, Lee

et al2 reported that 86% of patients experienced keloid-

associated pruritis and 46% experienced pain, with the itch

occurring predominantly at the edge and the pain occurring

mostly at the center of the keloid. Some keloids and

hypertrophic scars have a pink or red appearance with

notable telangiectasias. Often, the erythematous feature of

these lesions is the cause of significant cosmetic concern.

For unclear reasons, keloids occur on the chest,shoulders, upper back, back of the neck, and earlobes more

frequently.3 Massive keloids have been described secondary

to severe burn trauma,4 and in one case, a 1.8-kg keloid was

removed from the arm at the site of vaccination.5 Some

authors believe that keloids occur primarily in areas of high

skin tension,1 but exceptions to this rule suggest this may be

an oversimplification. Keloids appear rarely on the palms6

or soles,7,8 areas where we would expect significant skin

0738-081X/$ see front matterD 2007 Elsevier Inc. All rights reserved.

doi:10.1016/j.clindermatol.2006.09.009

* Corresponding author. Tel.: +1 206 598 2112; fax: +1 206 598 2112.

E-mail address: [email protected] (D. Berg).

Clinics in Dermatology (2007) 25, 2632

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tension. In addition, one of the most commonly affected

sites, the earlobe,9 is under minimal tension. Keloids have

been reported on the genitals, and in one case, a large keloid

extended from the labius majora to the mons pubis

secondary to trauma during childhood, a site unlikely to

be under significant tension.10-12 At least 70 cases of corneal

keloids after corneal trauma have been reported.13

Pathogenesis

The pathogenesis of keloid formation is poorly understood,

but keloids generally occur after injury or inflammation of the

skin in predisposed individuals. Commonly reported causes of

keloids include acne, folliculitis, chicken pox, and vaccina-

tions in addition to more obvious trauma (such as, earlobe

piercing, lacerations, or surgical wounds). Keloids may

develop as early as 1 to 3 months after trauma or inflammation,

but some may occur up to 1 year after the inciting event.1

Keloids generally do notoccurwith small needle sticks such as

local anesthetic injection unless they provoke inflammation(eg, vaccination sites). In one study, approximately 10% of

Taiwanese teenagers who received BCG vaccination were

reported to have a keloid at the injection site.14 Occasionally,

patients may report the spontaneous development of a keloid,

but because keloids represent the end product of aberrant

wound healing, this likely represents a lack of recall or trivial

trauma that was unnoticed by the patient.

Fibroblasts derived from keloids overproduce type I

procollagen, express higher levels of vascular endothelial

growth factor (VEGF), transforming growth factor-(TGF-)

b1/b2, platelet derived growth factor-(PDGF-)a receptors,

and have reduced growth factor requirements in vitro.15

Ladin et al reported that keloidal fibroblasts have lower rates

of apoptosis, and others have demonstrated a down-regula-

tion of apoptosis-related genes.16,17 Cultured keloidal fibro-

blasts have been found to have increased production of

collagen and matrix metalloproteinases compared with

normal dermal fibroblasts.18 The proliferation rate of keloid

fibroblasts is increased compared with hypertrophic scars.19

A built-in negative feedback mechanism, as yet not well

understood, prevents an excessive buildup of fibroblasts in

normal scars. Bronson et al20 reported that fibroblasts derived

from mature scars were able to suppress the in vitro

proliferation of fibroblasts in normal wound healing. As

such, it seems quite plausible that aberrant healing of woundsin hypertrophic scars and keloids is secondary to an inability

to activate or respond to the negative feedback mechanism in

place to suppress fibroblast activity. In this setting, fibroblasts

would essentially be allowed to brun-amok,Q resulting in

raised, enlarged, and cosmetically significant scars.

Epidemiology

Epidemiologic data on hypertrophic and keloidal scars

are limited but suggest differences among racial groups with

higher rates of keloids in blacks, Hispanics, and Asians.

Overall, the risk of developing keloids is approximately 15

times higher in dark-skinned individuals compared with

whites.1 The incidence of keloids in blacks and Hispanics

varies from 4.5% to 16%, with higher incidences during

puberty and pregnancy.21 A slight female predominance is

noted for keloids, but this appears to reflect the increase in

earlobe piercing among this group.

22

Genetics

The etiology of keloids likely involves genetic and

environmental factors. Although many cases occur sporad-

ically, a positive family history is not uncommon. There are

no clearly defined genetic loci conferring risk for keloids.

Bayat et al23 described an aggressive keloid variant in 3

families of African ethnic origin resulting in severe scarring.

Marneros et al24 described the pedigree analysis of 14

families with multiple affected members and suggested an

autosomal dominant with incomplete penetrance inheritancepattern based on their data. Despite significant limitations to

their study (small number of pedigrees, use of multiple

ethnicities, and elimination of certain members from

analysis), their data are still informative in demonstrating

that multiple families may have keloidssuggesting the

existence of at least some form of genetic susceptibility.

Corroborating common clinical experience, their data

demonstrated wide clinical variance of keloid development

within families, with some family members having larger,

whereas others having smaller keloids. Two rare syndromes

have been associated with keloid formation, namely,

Rubinstein-Taybi (OMIM 180849) and Goeminne syn-drome (OMIM 3134300).

To date, no susceptibility genes for keloid formation have

been identified. The examination of TGF-b1, b2, b3, and

TGF-b receptor polymorphisms has not yielded any

statistically significant associations with keloids in case

control studies.25-28 Difficulty in identifying bkeloid genesQ

among patients with keloids may reflect genetic heteroge-

neity, whereby different genes contribute to keloid forma-

tion in different families. As with many genetic diseases,

even inheritance of the same disease genes can be associated

with a variable phenotype, either because of differential

expression of alleles, genomic imprinting, methylation

effects, or even stochastic processes. cDNA microarray

analysis evaluating the differential gene expression among

keloids and normal scars or even normal skin may shed light

on the genetic control of these lesions.29

Histopathology

Histologically, keloids are characterized by increased

collagen and glycosaminoglycan content.30 There are

whorls of thickened hyalinized collagen bundles that are

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classically described as keloidal collagen.14 This irregular

orientation of collagen is distinct from normal tissue where

collagen bundles are in parallel to the epidermis. In an

attempt to distinguish the pathology of keloids from

hypertrophic scars, Lee et al14 analyzed 40 keloid specimens

from 29 patients and 10 hypertrophic scars from 9 patients.

In their analysis, they reported that keloidal collagen was

rarely seen in hypertrophic scars. Because keloidal collagenis not always seen in keloids, they found that the following

features favored keloid rather than hypertrophic scar: the

absence of prominent vertically oriented blood vessels, the

presence of a tongue-like advancing edge underneath

normal-appearing epidermis and papillary dermis, a hori-

zontal fibrous band in the upper reticular dermis, and a

prominent fascia-like band.14 They also found thata-smooth

muscle antigen (SMA) expression was not able to distinguish

between hypertrophic scar and keloid.

Management of keloids

Numerous therapies for keloids have been described with

varying degrees of clinical and scientific support for their

efficacy. The most commonly used treatments with possibly

the most evidence of efficacy include intralesional steroid

injection, surgical excision, cryotherapy, laser removal,

radiotherapy, and silicon gel sheeting. Less commonly used

treatments, but with some evidence of efficacy and possible

promise, include topical imiquimod and antimetabolites

(including 5-fluorouracil [5-FU] and bleomycin). Other

modalities have been mentioned as possible treatments,

and these include pressure therapy, retinoids, calcium

channel blockers, mitomycin C,

31,32

and antihistamines.Interferon injections have shown some promise in some

older studies (reviewed in Mustoe et al33), but a recent study

showed minimal efficacy of interferon alpha-2b.34

Intralesional steroid injection

Because of its ease of use, high degree of tolerability, and

effectiveness in reducing symptoms, intralesional steroid

injections are one of the most common modes of therapy for

keloids. Triamcinolone acetonide or Kenalog (Bristol-Myers

Squibb, Princeton, NJ) is commonly used at a concentration

of 10 to 40 mg/mL, depending on the size of the lesion.

Most of the data evaluating intralesional steroid injections

come from studies done 3 to 4 decades ago,35-38 with most

studies reporting less than a 50% recurrence rate.39

Concentration of Kenalog is necessarily higher for keloids

than other injections. In our practice, we start at 40 mg/mL.

Multiple injections every 4 to 6 weeks may be required.

Intralesional steroid injections may help flatten, soften, and

decrease symptoms of keloids, but it rarely results in

complete and long-term resolution. There are well-known

complications of intralesional steroid use, which include the

development of telangiectasias, skin atrophy, and hypo- or

hyperpigmentation. The injections can be quite painful, and

for larger lesions, pretreatment with eutectic mixture of local

anesthetics (EMLA) or the addition of lidocaine may help

alleviate injection-associated pain.22 Triamcinolone aceto-

nide is reported to inhibit human fibroblast growth in

vitro.40 This negative effect on fibroblast mitogenesis, as

well as collagen synthesis, may be a reflection of the

reported decrease in TGF-b1 production and increase in

beta-fibroblast growth factor (bFGF) production in fibroblasts treated with triamcinolone acetonide.41 Because of

pain of injection and concern about repeated injection of

large doses of corticosteroids, intralesional injection is

difficult to use for very large or multiple keloids.

Surgical excision

Surgical excision of keloids in most of the cases is not

curative. Recurrence rates after excision range between 45%

and 100%.33 Given this high recurrence rate, surgical

excision without adjuvant therapy should be considered

with caution. Excision often results in a longer scar than the

original keloid, and recurrence in this new area of traumacan lead to a larger keloid.42 Adjuvant therapies to consider

include many of the alternative monotherapies available,

such as postexcisional steroid injections. Small uncontrolled

studies suggest that topical imiquimod treatment may help

to reduce the recurrence rate, but these data are limited.43

Because some investigators suggest that excessive wound

tension may be associated with keloid formation, it is

advisable to ensure wound edge closure under minimal

tension. Care should be taken to follow relaxed skin tension

lines with aseptic technique and to obtain maximal wound

eversion.44 It is prudent to avoid unnecessary or elective

cosmetic procedures on patients with a history of keloid or

hypertrophic scar formation.45

Cryotherapy

Cryotherapy for keloids has been used for decades, and

smaller lesions are most responsive to this form of therapy.

Patients may have considerable pain with this mode of

treatment and may not come back for additional treatments

secondary to pain and prolonged healing.22 Multiple treat-

ments may be necessary, and hypopigmentation in darker-

skinned patients is a potential concern.46 In one in vitro

model, cryotherapy was found to modify collagen synthesis

and keloidal fibroblast differentiation toward a normal

phenotype.47 Lahiri et al48 favor a combination of steroidinjection followed by cryotherapy and then by steroid

injection, suggesting that the edema after thawing facilitates

further steroid injection.

Radiotherapy

In vitro analysis of radiation treatment on keloid

fibroblasts demonstrated an increase in apoptosis of these

cells.49 A number of studies in the literature using postexci-

sional radiotherapy with long-term follow-up have been

described.50-53 Unfortunately, there is no standardized

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radiotherapy dose, energy, or timing, making comparisons

between studies difficult. Nonetheless, radiotherapy has

demonstrated effectiveness in preventing keloid recurrence,

and the techniques used include superficial x-rays, electron

beam, and low- or high-dose-rate brachytherapy.53 Adjuvant

radiotherapy administered immediately after surgical exci-

sion is one of the most effective treatments available with

efficacy rates ranging from 65% to 99%.

54

The recurrencerate of keloids drops to less than 20% for radiotherapy used

after surgical excision.52 In a retrospective analysis with up

to 5-year outcome data, single-fraction radiotherapy within

24 hours of extralesional excision was evaluated in 80

keloids from 80 patients.50 At 5 years posttreatment, 20

(25%) of 80 were lost to follow-up, but of the 60 patients

analyzed, 79% and 86% of earlobe and chest keloids,

respectively, did not recur. Side-effects were transient

erythema and hyperpigmentation. In a separate retrospective

study of 147 keloids treated with 15-Gy electron beam

irradiation and followed for more than 18 months, the

overall recurrence rate was 32.7%.51

Ionizing therapy does carry some risks of carcinogenesis;

thus, it is important to warn patients that although low, the

risk of malignancy is theoretically possible. There are only a

few cases in the literature discussing a potential association

of malignancy with radiotherapy of keloids. Botwood et al55

described a case of bilateral breast cancer in a patient treated

30 years earlier for chest wall keloids. It is unclear whether

this malignancy was associated directly with the radiation

therapy, and it should be noted that breast cancer is not an

uncommon malignancy in women.56 A case of thyroid

carcinoma occurring 8 years after the treatment of a chin

keloid in an 11-year-old child was reported,57 but some

questions regarding causation were raised in a separatereport.55 Although the risks of carcinogenesis are not well

understood, some investigators recommend radiotherapy

only in patients aged 21 years or older and in those who

have failed previous excisional treatments.50

Lasers

A variety of lasers have been used for the treatment of

keloids, but all with limited effectiveness. Carbon dioxide

and argon lasers are not frequently used because recurrence

rates from this therapy alone are greater than 90%.42 The most

encouraging results have been obtained with the 585-nm

pulsed dye laser. Nonoverlapping laser pulses at fluencies

ranging from 6.0 to 7.5 J/cm2 (7-mm spot) or from 4.5 to 5.5

J/cm2 (10-mm spot) are recommended.58 Multiple treatments

(N2) may achieve better scar resolution.59 Combining pulsed

dye laser treatment with intralesional steroid may actually

make the scars more soft and edematous, facilitating the

penetration of the steroid.60 Kuo et al61 reported that flash-

lamp pulsed dye laser may actually induce keloid regression

by suppressing keloid fibroblast proliferation and induction

of apoptosis. These investigators also showed that pulsed

dye laser therapy was associated with down-regulation of

TGF-b1 expression and up-regulation of matrix metal-

loproteinase 13 (MMP-13) activity.62 Kumar et al63 studied

the effect of Nd:YAG laser irradiation on 17 patients with

keloids and reported full flattening in 60% at 3 months, with

complete resolution of the remaining patients achieved by

intralesional triamcinolone injection. At 18 months to 5 years

follow-up, 82% were keloid-free.

Silicone gel sheeting

Silicone gel dressings are effective when used after

surgical excision for preventing the recurrence of hypertro-

phic scars and keloids in 70% to 80% of cases.64 The gel

sheets have been reported to soften scars and decrease scar

size, erythema, and symptoms, including pain and itching.65

Based on current data, an international expert panel recom-

mended silicone gel sheet therapy as a first-line prophylaxis

beginning soon after surgical excision and continuing for at

least 1 month.33 The silicone gel sheeting shouldbe applied as

soon as reepithelialization is achieved, and the sheet should be

worn at least 12 hours per day.1

This requirement can makepatient compliance an issue. The sheets may be washed and

reapplied, with each sheet lasting approximately 10 to 12

days.66 A comparison of silicone versus nonsilicone gel

sheets in 26 patients with 41 hypertrophic scars or keloids

revealed that nonsilicone gel sheets were just as effective in

reducing scar size, induration, and symptoms.65 This suggests

that the occlusive nature of gel sheets, which is believed to

function in increasing the hydration of the scars, and not the

silicone itself, provides some benefit.

Imiquimod treatment

Imiquimod is anb

immune response modifierQ

known toup-regulate proinflammatory cytokines, including TNF-a,

when applied topically. Because TNF-a reduces fibroblast-

mediated collagen production, Berman and Kaufman43 and

Berman and Villa67 studied the effect of imiquimod 5% after

surgical excision of keloids. In 12 patients, after surgical

excision, imiquimod 5% cream was applied nightly for

8 weeks to the suture line and surrounding area. Side-effects

included itching, burning, pain, and blisters. Follow-up was

limited to 24 weeks, but in this time, no recurrence was seen.

In a separate, small, and uncontrolled study, also limited to

24 weeks follow-up, postsurgical imiquimod therapy of

8 earlobe keloids resulted in 25% recurrence.68 In that study,

4 additional patients underwent bilateral paired comparisons,

and 2 of these patients (50%) remained recurrence-free in the

imiquimod-treated areas, and those with recurrences were

treated with intralesional steroid. Because keloids may recur

with a median of more than 12 months after treatment, some

investigators have suggested that follow-up for any keloid

intervention should extend to at least 1 year,69 and others

have recommend follow-up for at least 2 to 3 years.56 The

uncontrolled and small sample sizes, as well as short follow-

up in existing studies, mean that imiquimod remains having

uncertain benefit for keloids at this time.


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Antimetabolites

5-Fluorouracil

5-Fluorouracil is a pyrimidine analog that is used as an

antimetabolite in cancer chemotherapy. 5-Fluorouracil is

converted intracellularly to its active substrate, which inhibits

DNA synthesis by competing with uracil incorporation.70

Keloid fibroblasts show increased proliferation and thus are a

target for 5-FU suppression when applied topically.71Nanda

and Reddy72 studied 28 patients with one or more keloids of

6- to 15-year duration. Each patient was treated weekly with

5-FU (50 mg/mL) for 12 weeks, and response to therapy up to

24 weeks was evaluated on the basis of patient satisfaction,

photographic record, and an independent clinical observer.

Symptoms of pain and pruritis resolved in most of the patients

(22/28), and a significant decrease in size was noted in more

than 70% of patients. The side-effects were pain at the

injection site (100%), ulceration (21.4%), and burning

sensation (7.1%).72 Gupta and Kalra73 studied 5-FU in 24

Indian patients and reported that approximately half of

patients had more than 50% flattening. Interestingly, onlyone of their patients had ulceration, but 100% had hyperpig-

mentation. In another study of 20 patients receiving weekly

intralesional injections of 5-FU (50 ng/mL), 85% showed

greater than 50% improvement at 12 months follow-up.74 In

that study, 100% of patients experienced pain and hyperpig-

mentation, and 6 of 20 experienced tissue sloughing. A

disadvantage of 5-FU treatment is the requirement for close

blood count monitoring because systemic 5-FU has been

associated with anemia, leukopenia, and thrombocytopenia.

Treatment should be avoided in pregnant and lactating

women and in patients with bone marrow suppression or

severe concurrent infections.70

Bleomycin

Espana et al75 applied bleomycin at a concentration of

1.5 IU/mL to keloids and hypertrophic scars in 13 patients with

a multiple-puncture method. These investigators reported

greater than 75% flattening of the scars in all cases, with

2 patients with recurrence at 10 and 12 months after the last

infiltration. In a separate preliminary study of 14 patients,

Saray and Gulec76 evaluated the efficacy and safety of

intralesional jet injection of bleomycin as therapy for resistant

keloids and hypertrophic scars. A total of 2 to 6 treatment

sessions were required to achieve flattening, and no re-

currences were noted with a mean follow-up duration of19 months. This form of therapyneeds additional investigation.

Combination therapy

Because of the lack of definitive monotherapy for

keloids, combination therapy may provide advantages by

acting on different pathogenic factors. The role of adjuvant

therapy after surgery has been noted above. Lahiri et al48

described the use of intralesional triamcinolone acetonide

followed by cryotherapy in the treatment of keloids. A

separate group reported that the combination of cryotherapy

and corticosteroid injections improved symptoms of keloids

and had a greater reduction of keloid thickness compared

with either therapy alone.77 Akoz et al21 recommend the

combination of surgical excision followed with triamcino-

lone acetonide injection, silicone gel sheeting, and pressure

for the treatment of earlobe keloids.

Prevention

Prevention of keloid formation is a key factor to consider

in keloid management. The clinician should be aware of risk

factors associated with keloid development, which include

previous keloids, family history of keloids, tension at site of

trauma, and dark skin.22 Some clinicians feel that one of the

greatest risk factors for keloid development is a wound

closed by secondary intention in a susceptible host. Patients

with a previous keloid or other risk factors should avoid

body piercing and elective cosmetic procedures. In a recent

randomized controlled trial evaluating the efficacy of paper

tape on preventing hypertrophic scar formation after

cesarean delivery, at 12 weeks, 41% of the control group

(who received no postoperative intervention) developed

hypertrophic scars compared with none in the treatment

group (who applied paper tape to their scars for 12 weeks). 78

In the treatment group, after removal of the tape, one patient

developed a hypertrophic scar and 4 developed stretched

scars. Although the authors concluded that prevention of

hypertrophic scarring was mediated by its ability to

eliminate scar tension, other factors such as occlusion and

hydration cannot be dismissed.

Conclusions

bNormalQ wound healing is a complex coordinated

process that has evolved to restore tissue integrity.

Abnormal wound healing may lead to excessive scar

formation, which has both functional and psychosocial

implications. Elucidation of the molecular pathways lead-

ing to excessive scar formation will undoubtedly open up a

host of opportunities for therapeutic intervention. Over the

last decade, the introduction of recombinant growth factors

like epidermal growth factor, basic fibroblast growth factor,

and platelet-derived growth factor has brought great

optimism to promote normal wound healing. Prevention

is paramount, and combination therapy will likely prove to

be most effective over any single modality in the treatment

of keloids.

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