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Current Progress in Keloid Research and Treatment

Paris D Butler, MD, Michael T Longaker, MD, MBA, FA C S, George P Yang, MD, PhD, FA C S

Keloids represent a form of pathologic wound healing af-fecting a substantial segment of the US population. Theyare more common among African-American, Asian-

American, Latin-American, and other darker pigmentedethnicities. They represent a form of abnormal woundhealing in genetically susceptible individuals, with upwardsof 15% of the population at risk.1-3 The genetic nature ofkeloids is underscored by the recent identification usinglinkage analysis of regions of the human genome highlycorrelated with keloid formation in two pedigrees with fa-milial keloids. The regions identified were in two separate,unrelated locations on the human genome, underscoring

the complex and multivariable pathogenesis of this disease.The regions identified still encompass several centimorgansof DNA and do not readily lead to identification of anysingle gene that might be causative of keloids.4

Keloids are benign dermal fibroproliferative tumorsunique to humans with no malignant potential.2,5-8 Theyoccur at areas of cutaneous injur y that do not regress andgrow continuously beyond the original margins of thescar.1,2 The majority of keloids lead to considerable cos-metic defects, but can grow large enough to become symp-tomatic by causing deformity or limiting joint mobility.

Alibert, in 1806, coined these abnormal scars with the

name cheloide, derived from the Greek word chele, or crabsclaw, to describe the lateral growth of tissue into neighbor-ing skin.9 By definition, keloids are scars that continue togrow and extend beyond the confines of the original

wound.2,6-8 In contrast to hyper trophic scars, which staywithin the boundaries of the original wound and increasein size by pushing out the edge of the scar, keloids invadethe skin beyond the perimeter of the original wound with aleading edge that is often er ythematous and pruritic.2 Someresearchers believe they represent an inability to halt the

wound-healing process.Keloids and hypertrophic scars are not always easy to

differentiate, and there has been a great deal of research

describing in detail the clinical and morphologic differ-ences between them. As a result, a scar classification schemehas been established in the plastic surger y literature, whichdescribes wounds ranging from normal mature scar to ma-

jor keloid, with linear and widespread hypertrophic scarsplaced some where near the middle (Table 1).2,10 Both le-sions represent aberrations in the fundamental processes of

wound healing, where there is an obvious imbalance be-tween the anabolic and catabolic phases.

HISTOPATHOLOGY

Histologically, keloids have a normal epidermal layer,

abundant vasculature, increased mesenchymal density,as manifested by a thickened dermis, and increasedinflammator y-cell infiltrate when compared with normalscar tissue.2,11,12 The reticular layer of the dermis consistsmainly of collagen and fibroblasts, and injur y to this layer isthought to contribute to formation of keloids. Collagenbundles in the dermis of normal skin appear relaxed and inan unordered arrangement; collagen bundles are thickerand more abundant in keloids, yielding acellular, node-likestr uctures in the deep dermal region.13The most consistenthistologic distinguishing characteristic of keloids is thepresence of large, broad, closely arranged collagen fibers

composed of numerous fibrils.14 In addition to collagen,proteoglycans are another major extracellular matrix(ECM) component deposited in excess amounts in keloidscars.15,16

Generally, there are four histologic features that are con-sistently found in keloid specimens that are deemed patho-gnomonic for their diagnosis. They are the presence ofkeloidal hyalinized collagen, a tongue-like advancing edgeunderneath normal-appearing epidermis and papillar y der-mis, horizontal cellular fibrous bands in the upper reticulardermis, and prominent fascia-like fibrous bands (Table 2).17

Altered wound healing response

Wound repair involves a complex series of events that be-gins at the moment of injur y and continues in a highlysystematic manner. Divided into three distinct phases, in-flammator y, proliferative, and remodeling, the wound-healing process can take months to complete. At the onsetof the inflammator y phase, platelet degranulation is re-sponsible for release and activation of numerous cytokines,

which act as chemotactic agents for recruitment of inflam-matory cells, epithelial cells, and fibroblasts. It has been

Competing Interests Declared: None.

Received August 3, 2007; Revised November 2, 2007; Accepted on Decem-ber 3, 2007.From the Department of Surgery, Stanford University School of Medicine,Stanford, CA (Butler, Longaker,Yang), Department of Surgery, University ofVirginia School of Medicine, Charlottesville, VA (Butler), and the Palo AltoVA Health Care System, Palo Alto, CA (Yang).Correspondence address: George P Yang, MD, Department of Surgery, Stan-ford University School of Medicine, 257 Campus Dr, M/C 5148, Stanford,CA 94305-5148. email:[email protected]

731 2008 by the American College of Surgeons ISSN 1072-7515/08/$34.00

Published by Elsevier Inc. doi:10.1016/j.jamcollsurg.2007.12.001
mailto:[email protected]:[email protected]:[email protected]


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epidermis when compared with normal epidermis andeven higher expression of CTGF in the keloid tissue ex-tract.30 These findings reinforce a correlation betweenCTGF gene expression and skin sclerosis and support thehypothesis that TGF- plays an important role in thepathogenesis of fibrosis, as it is one of the major inducers ofCTGF.28 CTGF transcription is upregulated in KFs be-cause of increased activation of JNK, another target ofTGF- Smad-independent signaling.23 These combineddata suggest that Smad-independent pathways mightbe more important in keloid pathogenesis than Smad-dependent ones.

In addition to TGF- and CTGF, PDGF has also beenimplicated in the pathogenesis of keloid scars. PDGF is amajor growth factor present in serum and platelets thatis mitogenic and chemotactic for connective tissuecells.21,31-34 This growth factor also stimulates collagenaseproduction and synthesis of ECM components, such asfibronectin and hyaluronic acid.21,35-37 It has been shownthat when compared with NFs, KFs have heightened re-sponse to PDGF, which could be accounted for by elevatedlevels of PDGF -receptors in KFs.21 Additionally, thesame study exhibited that KFs exhibited a greater migra-tory response to all three isoforms of PDGF than NFs. Wehave highlighted three of the major growth factors thathave been implicated in keloid formation, but there are anumber of other growth factors and inflammatory me-diators that have been linked to keloid pathogenesis(Table 3).18,38-41

Mechanical strain

There have been clinical observations that wounds sub-jected to increased skin tension are more likely to formkeloids.42,43 Certain wound types have been noted to bemore likely to form keloids because of increased skin ten-sion, especially median sternotomies. Earlobe keloids areanother example where it has been hypothesized that skinirritation and tension from the weight of earrings contrib-ute to keloid formation. It is also known that subjecting

cells to mechanical force leads to formation of focal adhe-sion complexes, and integrins are believed to be one of theprimary receptors for mechanical force.42,44-46 Mechanicalstimulation is capable of inducing several cell functions,including stimulation of gene expression, protein synthe-sis, and proliferation.47-50 A recent study subjected bothnormal and keloid fibroblasts to mechanical strain and re-vealed thatKFs had increasedexpression ofTGF-1,TGF-2, and collagen I compared with NFs.42 Additionally,there was increased formation of focal adhesion complexesin KFs subjected to strain in comparison with NFs withincreased activation of focal adhesion kinase, a major sig-naling component of the focal adhesion complex. Thesestudies suggest another mechanism by which increased lev-els of profibrotic factors can be produced in KFs.42

Balance of anabolic and catabolic activities

In addition to the concern about aberrant signaling pathways, some groups have theorized that the increasedamount of ECM components found in keloids is a reflec-tion of both increased number and increased inherent met-abolic activity of these KFs. One study compared the totalprotein content and amount of endoplasmic reticulum inthe fibroblasts of keloid, normal, and hypertrophic scars asa means to evaluate their metabolic activity. Keloids hadelevated levels of both protein and endoplasmic reticulum

Table 2. Histologic Features Commonly Associated with Ke-loid and Hypertrophic Scars2,11-14,17

Presence of keloid collagen*

No flattening of overlying epidermis

No scarring of papillary dermis

Absence of prominent vertically oriented blood vessels

Presence of prominent disarray of fibrous fascicles/nodulesPresence of a tongue-like advancing edge underneath normal-

appearing epidermis and papillary dermis*

Horizontal cellular fibrous band in the upper reticular dermis*

Prominent fascia-like fibrous band*

*Features uniquely associated with keloid histology.

Table 3. Current Areas of Research in Keloid Pathogenesis

Areas of research Reference no.

Cytokines, growth factors and inflammatorymediators

TGF- 19,20

CTGF 22

PDGF 21IGF-1 38

VEGF 39

ECGF 40

PAI-1 41

PGE2 18

Keloid fibroblast metabolic activity 51

Mechanical strain and focal adhesioncomplexes 4250

Aberrant anabolic wound healing processes 52

Abnormal regulation of apoptosis secondaryto gene mutations

p53 2,11,54,55p63 8,11

p73 11

Keloid epithelial-mesenchymal signaling 5663

TGF-, transforming growth factor-; CTGF, connective tissue growth fac-tor; PDGF, platelet-derived growth factor; IGF-1, insulin-like growthfactor-1; VEGF, vascular endothelial growth factor; ECGF, epidermal;PAI-1, plasminogen activator inhibitor-1; PGE2, prostaglandin E2.

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when compared with its counterparts, suggesting that anincreased synthetic capacity can contribute to the excessECM found in keloid scars.51 It remains to be proven

whether the increased synthetic activity in KFs is the causeof keloids or just a result of other stimuli.

Normal wound healing requires a balance of catabolicand anabolic activities, especially during the remodelingphase, when new ECM components are secreted, althoughthere is some degradation of preexisting ECM. The major-ity of keloid research, to date, has focused primarily on theanabolic processes, but recently there has been increasedfocus on possible abnormalities in catabolic activity in thekeloid. Increasedaccumulation of ECM proteins in keloidsmight not just be a result of elevated synthesis, but rather adeficiency in their matrix degradation ability.

One study examined the synthesis of collagen, collage-nase, and the regulatory role of TGF- in KFs and NFs.Collagen synthesis was increased in KFs compared withcontrols; only minimal interstitial collagenase I was synthe-sized in KFs when compared with NFs.52Another studyfrom the dermatologic literature revealed that collagenaseproduction was lower in postburn hypertrophic scar fibro-blasts than in normal fibroblasts and is additionally re-duced by IGF-1.53These experiments suggest that the basicmechanism for growth of keloids is a change in the normalbalance of ECM secretion and degradation seen during

wound healing.

Abnormal regulation of apoptosis

Apoptosis, or programmed cell death, is an important com-ponent of wound healing. As with ECM production anddegradation, there is a balance of cell proliferation andapoptosis. It has been noted that regulation of apoptosisand proliferation in fibroblasts is altered in keloids.3,11 KFshave been shown to have a lower rate of apoptosis than NFsin multiple studies.8,54 Several genes have been implicatedin development of abnormal scars, including p53, p63, andp73, but data on p53 appears to be most intriguing.11Arecent study revealed that although the exact mechanism ofp53 expression in keloid formation has yet to be deter-mined, the level of p53 is highest in keloids when com-

pared with normal and hypertrophic scars.11

One groupreported findinga number of p53 mutations in keloids thatcould lead to decreased apoptosis, and it has been reportedthat there is less apoptosis in keloids compared with normalscars.3,11,55

Epithelial-mesenchymal signaling

Although much of the literature points to the fibroblast asthe main culprit in keloid pathology, there is increasingevidence that the histologically normal-appearing keratin-

ocytes interact with the fibroblasts to stimulate keloid for-mation. We are learning that epidermal homeostasis,growth, and differentiation are controlled in many ways byepithelial-mesenchymal interactions.56-59 It has long beenobserved thatproliferationandECMproductionof dermal

fibroblasts in a wound is suppressed after reepithelializa-tion. The secretory role of the epidermis, which is com-posed primarily of keratinocytes, is intriguing because notonly does it secrete autocrine proteins, but it also secretescytokines, in a paracrine fashion into the extracellular do-main to effect local proliferative, metabolic, and immuno-logic functions.56,60,61 The implication is that a feedbackloop is initiated by keratinocytes, which are responsible formediating some of the ECM production characteristics ofthe underlying fibroblasts and scar formation.56

One recent study compared the influence of keloid-derived keratinocytes (KKs) and normal keratinocytes

(NKs) on the growth and proliferation of fibroblasts in anin vitro serum-free coculture system. It revealed that there

was a considerable increase in proliferation seen in anyfibroblasts cocultured with KKs, as compared with NKcontrols.56 This strongly suggests that KKs might have animportant role in keloid pathogenesis by producing signalsthat stimulate the fibroblasts in the underlying dermis toproliferate or produce more ECM.56

Additionally, because it is well-documented that KFshave increased expression of TGF-, it had been hypothe-sized that KKs can also have aberrant expression of this

potent profibrotic factor. One study revealed that KKs incoculture with fibroblasts expressed more TGF-1, -3,and TGF- receptor than NKs. KFs cocultured with KKsexpressed more mRNA for TGF-1, -3, and TGF-1receptor andSmad2 thanNFs. Finally, KFs produced morecollagen 1, CTGF, and IGF-1 receptor when cocultured

with KKs compared with NKs.62A more recent study re-vealed that KKs produced more TGF-2 mRNA thanNKs, in response to serum stimulation.63

Combining these data suggests that keloid pathogenesislikely results from an exaggerated response to cellular stressand abnormal keratinocyte-fibroblast signaling, which

promotes this abnormal scar formation.62,63 Other datahave suggested that the leading edge of the keloid is differ-ent from the center where the process has already burnedout.This is reflected in the findingthat there is an increasedinflammatory infiltrate at the leading edge and the expres-sion of many profibrotic factors, including CTGF, is in-creased in the same location.This would suggest that treat-ment should be directed at that leading edge.64 Becausethere remains a lack of a successful animal model for keloidformation, the development of a model to allow additional

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investigation of these interactions would be extremely ben-eficial in deciphering the pathogenesis.

CURRENT THERAPIES AND

FUTURE PROSPECTS

Unfortunately, a single effective therapeutic regimen hasyet to be established for treatment of keloids. Prevention isan obvious answer, but it is not possible to forego vitaloperations because of a potential risk of keloids. Althoughthere is no single definitive treatment modality, there arenumerous therapeutic regiments that have been described,including occlusive dressings, compression therapy, intrale-sional steroid injections, cryosurgery, surgical excision, la-ser treatment, radiation therapy, interferon therapy, bleo-mycin, 5-flouracil, verapamil, imiquimod cream, TGF-3,interleukin-10, and combinations of all of these. Table 4provides a synopsis of these various regimens to review theactual scientifically based evidence and to provide someinsight into the options that are truly advantageous andappropriate for keloid treatment.

Both silicone and non-siliconebased occlusive dress-ings have been a widely used clinical option for keloids forthe last 30 years.65,66 Results from several studies have re-vealed 79% to 90% improvement in keloid scars with theuse of these occlusive dressing, complete resolution has notbeen noted.65,66 Pressure dressings have been another non-invasive treatment modality with wound improvement of70% to 90%, but once again complete resolution has notbeen shown.67 The advantage of both occlusive and pres-sure dressings is that although they might not completelyeliminate the keloid, they tend to be better tolerated inpediatric patients and adults who cannot tolerate the othermore invasive therapies.10

Surgical excision alone has been repeatedly proven to beineffective, with reported recurrence rates of 55% to100%.10,68-71 The combination of surgical excision withother modalities, such as corticosteroid injection,72,73 ste-roid injection with pressure dressing,74 x-ray therapy,75,76

interstitial radiation,77 single fraction radiation,78,79 tele-therapy radiation,80 and brachytherapy81 have revealed rel-atively good results, with 5-year recurrence rates reportedfrom 8% to 50%.

Various forms of radiotherapy have been attempted as amonotherapy for keloids, but remain quite controversialbecause of anecdotal reports of carcinogenesis after treat-ment.10,82As mentioned earlier, radiotherapy after surgicalexcision of keloids has shown some signs of promise,75-81

with no evidence of increased risk of malignancy.Laser therapy using argon, CO2, and pulse dye have

been repeatedly attempted during the last 40 years, butnone of them have proven to be efficacious. All three forms

of laser therapy, according to multiple studies, have recur-rence rates of upwards of 90%, showing little to nobenefit.83-85

Despite its side effects of pain at the therapeutic site andhypo- or hyperpigmentation, cryotherapy as a mono-

therapy has proven to be quite effective, with one studyrevealing that 73% of patients had substantial flattening oftheir keloid scars.86 Additionally, of those scars that didrespond, there were no recurrences reported. Cryotherapycombined with corticosteroid injections also had relativelygood results in one study, where 67% of patients had sub-stantial scar flattening and, once again, no recurrence ofthose scars that responded.87

Intralesional triamcinolone acetone injections, a type ofcorticosteroid, have been a relatively effective first-linetherapy for the treatment of keloids. Although, their exactmechanism remains unclear, one study revealed a slightly

less than 50% 5-year recurrence rate when triamcinoloneacetone was used as a monotherapy.72As mentioned earlier,it has increased efficacy when combined with both surgicalexcision72,73 and cryotherapy87; the need for multiple injec-tions, along with the side effects of injection pain, skinatrophy, telangiectasias, and altered pigmentation havecaused clinicians and researchers to continue to look forother means of treatment.

Several pharmacologic agents have recently emerged aspromising treatments for keloid scars. Only small studieshave taken place, but monotherapy with intralesional5-FU88 or bleomycin tattooing87,89 revealed moderate to

substantial scar flattening in 88% and 92% of treated pa-tients, respectively, and no recurrences in those scars thatinitially responded. There are also reports of several othermedications, when used in conjunction with surgical exci-sion, giving relatively successful results. Postsurgical in-tralesional interferon injections,73 intralesional verapamilinjections,90 and topical imiquimod cream91,92 resulted in54%, 44%, and up to 25% recurrence rates, respectively.Unfortunately, despite the success that has been seen withthese medications, all of them have been associated withvarious side effects, ranging from skin pruritus, to alteredpigmentation, to injection pain. Additionally, the studies

have also been relatively small in scope. It is quite apparentthat additional investigation is imperative to elucidatethose agents that have the absolute best efficacy, to deter-mine the appropriate dosages and most optimal timing ofadministration of those agents, and to ensure the preven-tion of those agents untoward side effects.

It is becoming increasingly obvious that failure of thesetreatments just highlights the essential problem in keloids;there is still no clear molecular mechanism defined for ke-loid development. Increased understanding at the molecu-



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Table 4. Summary of Keloid Treatment Modalities

Modality First author No. of treated keloids Wound improvement Recurrence of

Silicone occlusive dressing (6-moapplication)

Wong65 19 79% had substantial reduction inerythema, scar elevation, andpruritus

NA

Nonsilicone occlusive dressing(8-wk application)

Bieley66 21 90% had an average of 35%reduction in scar elevation.

67% had reduced erythema74% had reduced tenderness

NA

Pressure dressing (25 mmHg ofpressure, worn 824 h/d)

Robertson67 40 70% had 75100% reduction inscar elevation

NA

Surgical excision Estes68, Niessen69,Slemp70, Berman71

200 NA 55% (1

Cryotherapy Rusciani86 65 73% with complete flattening ofthe scar

0% recurrence aof the 73% that

Argon laser (488 nm) Hulsbergen83 45 Transient shrinkage of scar by20% in 50%

90% (1

CO2 laser (10,600 nm) Norris84 23 NA 95% (10

Pulse dye laser (585 nm) (13sessions)

Paquet85 11 Minimal improvement of erythema or pruritus

NA

Combined surgical excision andimmediate postop x-raytherapy

Sallstrom75 124 Subjectively, 92% had excellentimprovement

8% (1

Kovalic76 100 NA 27% (9

Combined surgical excision andimmediate postop singlefraction radiotherapy (10-Gygiven 24 h postop)

Ragoowansi78 80 NA 9% (116% (5

Meythiaz79 56 NA 10% (1

Combined surgical excisionimmediate postop interstitialradiotherapy (Iridium 192)

Escarmant77 855 Symptoms improved in 80%Good cosmetic result in 75%

21% (1


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Table 4. Continued


Combined surgical excision andimmediate postop cobalt 60teletherapy radiation (1,600cGy in 4 equal fractions of 400

cGy for 4 d)

Malaker80 47 NA 12.7% (6

Combined surgical excision andimmediate postop high-doserate brachytherapy (12 Gy in 4equal fractions of 300 cGy for24 h)

Guix81 147 Good cosmetic result in 88.4% 3.4% (7

High-dose-rate brachytherapyalone (18 Gy in 6 equalfractions of 300 cGy for 24 h)

Guix81 22 Good cosmetic result in 77% 13.6% (7

Intralesional corticosteroidinjection (triamcinoloneacetone) (1040 mg/mL 6-wkintervals)

Kiil72 37 Initial flattening of scar 30% (150% (5

Combined surgical excision andpostop corticosteroid injection(triamcinolone 1040 mg/mL,6-wk intervals)

Kiil72 15 Initial excellent healing 30% (150% (1

Davison73 26 Initial excellent healing 15% (2

Combined cryotherapy andcorticosteroid injection(triamcinolone 1040 mg/mL,

6-wk intervals for 3 mo)

Farahnaz87 22 67% had flattening of the scar49% were asymptomatic after

treatment

0% recurrence athe 67% that responded

Combined pulse dye laser andcorticosteroid injection(triamcinolone acetone) (1040 mg/mL 6-wk intervals)

Connell93 10 40% had decreased erythema60% had flattening of the scar70% had decreased pruritus

NA


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Table 4. Continued


5-Flouracil (5-FU) (16, 1-wkinterval, intralesional injection

(50150 mg)

Gupta88 24 33% had75% scar flattening50% had50% scar flattening

0% recurrence athe80% th

respondedBleomycin tattooing (1.5 IU/mL)

Espana89 15 46% had 100% scar flattening46% had90% scar flattening100% had some form of wound

improvement

15% (1

Farahnaz87 26 88% had reduction in lesion sizeand scar flattening

69% were subjectivelyasymptomatic after treatment

0% recurrence othat initially r

Combined surgical excision andpostop intralesional interferon-2b injection

Davison73 13 NA 54% (2

Combined surgical excision andpostop intralesional Verapamilhydrochloride injection

DAndrea90 22 NA 44% (18 mo) (bthese had smathan before tx

Combined surgical excision andpostop imiquimod 5% cream

wound application (daily for8 wk)

Martin-Garcia91 8 NA 25% (6

Stashower92 8 NA 0% (4

Combined surgical excision,

postop single corticosteroidinjection (triamcinolone 40mg/mL) and pressure earring

worn for 1 y

Jackson74 7 NA 42% (5

tx, treatment; NA, not applicable or addressed; postop, postoperative.


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lar level will lead to development of new therapies. Deter-mining how to control profibrotic growth factors,obtaining a better understanding of the immune responseto injury and the wound healing process, and developing amodel system to better understand the interactions in-volved in keloid biology will provide insight for the estab-lishment of more effective therapeutic options for thesepatients.

Author Contributions

Study conception and design: Butler, Longaker, YangAcquisition of data: Butler, Longaker, YangAnalysis and interpretation of data: Butler, Longaker, YangDrafting of manuscript: Butler, Longaker, YangCritical revision: Butler, Longaker, Yang

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