Current Progress in Keloid Research and Treatment
Paris D Butler, MD, Michael T Longaker, MD, MBA, FACS, George P Yang, MD, PhD, FACS
Keloids represent a form of pathologic wound healing af-
fecting a substantial segment of the US population. They
are more common among African-American, Asian-
American, Latin-American, and other darker pigmented
ethnicities. They represent a form of abnormal wound
healing in genetically susceptible individuals, with upwards
of 15% of the population at risk.1-3 The genetic nature of
keloids is underscored by the recent identification using
linkage analysis of regions of the human genome highly
correlated 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 centimorgans
of DNA and do not readily lead to identification of any
single gene that might be causative of keloids.4
Keloids are benign dermal fibroproliferative tumors
unique to humans with no malignant potential.2,5-8 They
occur at areas of cutaneous injury that do not regress and
grow continuously beyond the original margins of the
scar.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 crab’s
claw, to describe the lateral growth of tissue into neighbor-
ing skin.9 By definition, keloids are scars that continue to
grow and extend beyond the confines of the original
wound.2,6-8 In contrast to hypertrophic scars, which stay
within the boundaries of the original wound and increase
in size by pushing out the edge of the scar, keloids “invade”
the skin beyond the perimeter of the original wound with a
leading edge that is often erythematous and pruritic.2 Some
researchers 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
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 of
Virginia School of Medicine, Charlottesville, VA (Butler), and the Palo Alto
VA 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: gpyang@stanford.edu
© 2008 by the American College of Surgeons
Published by Elsevier Inc.
describing in detail the clinical and morphologic differ-
ences between them. As a result, a scar classification scheme
has been established in the plastic surgery literature, which
describes wounds ranging from normal mature scar to ma-
jor keloid, with linear and widespread hypertrophic scars
placed somewhere 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 increased
inflammatory-cell infiltrate when compared with normal
scar tissue.2,11,12 The reticular layer of the dermis consists
mainly of collagen and fibroblasts, and injury to this layer is
thought to contribute to formation of keloids. Collagen
bundles in the dermis of normal skin appear relaxed and in
an unordered arrangement; collagen bundles are thicker
and more abundant in keloids, yielding acellular, node-like
structures in the deep dermal region.13 The most consistent
histologic distinguishing characteristic of keloids is the
presence 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 keloid
scars.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 of
keloidal hyalinized collagen, a tongue-like advancing edge
underneath normal-appearing epidermis and papillary der-
mis, horizontal cellular fibrous bands in the upper reticular
dermis, 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 injury and continues in a highly
systematic manner. Divided into three distinct phases, in-
flammatory, proliferative, and remodeling, the wound-
healing process can take months to complete. At the onset
of the inflammatory 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
ISSN 1072-7515/08/$34.00
731 doi:10.1016/j.jamcollsurg.2007.12.001
732 Butler et al Progress in Keloid Research and Treatment J Am Coll Surg

Table 1. Scar Classification

Abbreviations and Acronyms Scar Description
CTGF ⫽ connective tissue growth factor Mature scar A light-colored, flat scar.
ECM ⫽ extracellular matrix Immature scar A red, sometimes pruritic or
KF ⫽ keloid fibroblast tender, slightly elevated scar in
KK ⫽ keloid keratinocyte the process of remodeling. Many
NF ⫽ normal fibroblast of these will mature normally
NK ⫽ normal keratinocyte with time, flatten, and assume a
PDGF ⫽ platelet-derived growth factor pigmentation that is similar to
TGF-␤ ⫽ transforming growth factor-␤ the surrounding skin.
Linear hypertrophic scar A red, elevated, sometimes pruritic
(eg, surgical/traumatic) scar confined to the border of
the original surgical incision.
proposed that keloid formation occurs because of the re- This usually occurs within weeks
sponse to inflammation by keloid-derived fibroblasts (KFs) after operation. These scars can
involving an abnormal secretion of proinflammatory me- increase in size rapidly for 3 to 6
months and then, after a static
diators and an abnormal response to other inflammatory
phase, begin to regress. They
signals.18 generally mature to have an
When compared with normal fibroblasts (NFs), a mul- elevated, slightly rope-like
titude of studies have revealed that KFs have increased ex- appearance with increased
pression of many of these potent cytokines, including width, which is variable. The
full maturation process can take
transforming growth factor-␤ (TGF-␤),19,20 platelet-
up to 2 years.
derived growth factor (PDGF),21 and connective tissue
Widespread hypertrophic A widespread red, elevated,
growth factor (CTGF) (Table 3).22 In addition to increased scar (eg, burn) sometimes pruritic scar that
cytokine production, KFs also increase transcription of remains within the borders of
many of the receptors for these factors to a substantial the burn injury.
degree over NFs. Theoretically, this leads to aberrant heal- Minor keloid A focally elevated, pruritic scar
ing, as the response to these factors enhances cellular re- extending over normal tissue.
This can develop up to 1 year
cruitment and, as a result, causes excess synthesis of colla-
after injury and does not regress
gen, proteoglycans, and other ECM components. Several on its own. Simple surgical
groups have demonstrated this increase in ECM compo- excision is often followed by
nents as they evaluated the molecular composition of ab- recurrence. Typical sites include
normal scars and determined that keloids have increased earlobes and anterior chest.
levels of acid soluble collagen, proteoglycans, and water Major keloid A large, elevated (⬎0.5 cm) scar,
possibly painful or pruritic and
when compared with normal and hypertrophic scars.13
extending over normal tissue.
This can continue to spread for
AREAS OF RESEARCH years.
Modified from: Mustoe TA, Cooter RD, Gold MH, et al. International
Growth factors clinical recommendations on scar management. Plast Reconstr Surg 2002;
Currently, the majority of keloid research involves the eval- 110:560–571, with permission; page 561, Table I.
uation of protein factors and the involved upstream and
downstream signaling pathways that can have a role. and Smad-independent pathways and much work has gone
TGF-␤, CTGF, and PDGF function as traditional growth into determining which pathways are involved in fibrosis.27
factors that bind to a cognate receptor and trigger a number TGF-␤2 is upregulated in keloid fibroblasts through the
of signaling pathways. p38 kinase pathway and TGF-␤ can activate p38 kinase
Historically, TGF-␤ and CTGF have been known to be through Smad-independent pathways implying there is
potent profibrotic factors and there has been an appreciable positive autoregulation.19
amount of data linking them with keloid pathogenesis.19 It has been well-documented that CTGF (also known as
Differential TGF-␤ isoform expression occurs in fibro- CCN2) mRNA has elevated expression in the various types
blasts during skin development, and during fetal and post- of mesenchymal cells of fibrotic disorders, such as ke-
natal wound healing.23-26 It has been reported that TGF-␤1 loids, pulmonary fibrosis, eosinophilic fasciitis, nodular
and TGF-␤2 have profibrotic functions and TGF-␤3 has fasciitis, Dupuytren’s contracture, renal fibrosis, and liver
antifibrotic functions.23,26 TGF-␤–signaling transduction cirrhosis.28,29 A recent study revealed that there was in-
pathways are now known to involve both Smad-dependent creased localization of CTGF in the basal layer of keloid
Vol. 206, No. 4, April 2008
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/nodules
Presence 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.
epidermis when compared with normal epidermis and
even higher expression of CTGF in the keloid tissue ex-
tract.30 These findings reinforce a correlation between
CTGF gene expression and skin sclerosis and support the
hypothesis that TGF-␤ plays an important role in the
pathogenesis of fibrosis, as it is one of the major inducers of
CTGF.28 CTGF transcription is upregulated in KFs be-
cause of increased activation of JNK, another target of
TGF-␤ Smad-independent signaling.23 These combined
data suggest that Smad-independent pathways might
be more important in keloid pathogenesis than Smad-
dependent ones.
In addition to TGF-␤ and CTGF, PDGF has also been
implicated in the pathogenesis of keloid scars. PDGF is a
major growth factor present in serum and platelets that
is mitogenic and chemotactic for connective tissue
cells.21,31-34 This growth factor also stimulates collagenase
production and synthesis of ECM components, such as
fibronectin and hyaluronic acid.21,35-37 It has been shown
that when compared with NFs, KFs have heightened re-
sponse to PDGF, which could be accounted for by elevated
levels of PDGF ␣-receptors in KFs.21 Additionally, the
same study exhibited that KFs exhibited a greater migra-
tory response to all three isoforms of PDGF than NFs. We
have highlighted three of the major growth factors that
have been implicated in keloid formation, but there are a
number 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 form
keloids.42,43 Certain wound types have been noted to be
more likely to form keloids because of increased skin ten-
sion, especially median sternotomies. Earlobe keloids are
another example where it has been hypothesized that skin
irritation and tension from the weight of earrings contrib-
ute to keloid formation. It is also known that subjecting
Butler et al Progress in Keloid Research and Treatment 733
Table 3. Current Areas of Research in Keloid Pathogenesis
Areas of research Reference no.
Cytokines, growth factors and inflammatory
mediators
TGF-␤ 19,20
CTGF 22
PDGF 21
IGF-1 38
VEGF 39
ECGF 40
PAI-1 41
PGE2 18
Keloid fibroblast metabolic activity 51
Mechanical strain and focal adhesion
complexes 42–50
Aberrant anabolic wound healing processes 52
Abnormal regulation of apoptosis secondary
to gene mutations
p53 2,11,54,55
p63 8,11
p73 11
Keloid epithelial-mesenchymal signaling 56–63
TGF-␤, transforming growth factor-␤; CTGF, connective tissue growth fac-
tor; PDGF, platelet-derived growth factor; IGF-1, insulin-like growth
factor-1; VEGF, vascular endothelial growth factor; ECGF, epidermal;
PAI-1, plasminogen activator inhibitor-1; PGE2, prostaglandin E2.
cells to mechanical force leads to formation of focal adhe-
sion complexes, and integrins are believed to be one of the
primary receptors for mechanical force.42,44-46 Mechanical
stimulation is capable of inducing several cell functions,
including stimulation of gene expression, protein synthe-
sis, and proliferation.47-50 A recent study subjected both
normal and keloid fibroblasts to mechanical strain and re-
vealed that KFs had increased expression of TGF-␤1, TGF-
␤2, and collagen I compared with NFs.42 Additionally,
there was increased formation of focal adhesion complexes
in KFs subjected to strain in comparison with NFs with
increased activation of focal adhesion kinase, a major sig-
naling component of the focal adhesion complex. These
studies 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 path-
ways, some groups have theorized that the increased
amount 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 total
protein content and amount of endoplasmic reticulum in
the fibroblasts of keloid, normal, and hypertrophic scars as
a means to evaluate their metabolic activity. Keloids had
elevated levels of both protein and endoplasmic reticulum
734 Butler et al Progress in Keloid Research and Treatment
when compared with its counterparts, suggesting that an
increased synthetic capacity can contribute to the excess
ECM found in keloid scars.51 It remains to be proven
whether the increased synthetic activity in KFs is the cause
of keloids or just a result of other stimuli.
Normal wound healing requires a balance of catabolic
and anabolic activities, especially during the remodeling
phase, when new ECM components are secreted, although
there is some degradation of preexisting ECM. The major-
ity of keloid research, to date, has focused primarily on the
anabolic processes, but recently there has been increased
focus on possible abnormalities in catabolic activity in the
keloid. Increased accumulation of ECM proteins in keloids
might not just be a result of elevated synthesis, but rather a
deficiency 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 with
controls; only minimal interstitial collagenase I was synthe-
sized in KFs when compared with NFs.52 Another study
from the dermatologic literature revealed that collagenase
production was lower in postburn hypertrophic scar fibro-
blasts than in normal fibroblasts and is additionally re-
duced by IGF-1.53 These experiments suggest that the basic
mechanism for growth of keloids is a change in the normal
balance 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 and
degradation, there is a balance of cell proliferation and
apoptosis. It has been noted that regulation of apoptosis
and proliferation in fibroblasts is altered in keloids.3,11 KFs
have been shown to have a lower rate of apoptosis than NFs
in multiple studies.8,54 Several genes have been implicated
in development of abnormal scars, including p53, p63, and
p73, but data on p53 appears to be most intriguing.11 A
recent study revealed that although the exact mechanism of
p53 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 group
reported finding a number of p53 mutations in keloids that
could lead to decreased apoptosis, and it has been reported
that there is less apoptosis in keloids compared with normal
scars.3,11,55
Epithelial-mesenchymal signaling
Although much of the literature points to the fibroblast as
the main culprit in keloid pathology, there is increasing
evidence that the histologically normal-appearing keratin-
J Am Coll Surg
ocytes interact with the fibroblasts to stimulate keloid for-
mation. We are learning that epidermal homeostasis,
growth, and differentiation are controlled in many ways by
epithelial-mesenchymal interactions.56-59 It has long been
observed that proliferation and ECM production of 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 not
only does it secrete autocrine proteins, but it also secretes
cytokines, 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 feedback
loop is initiated by keratinocytes, which are responsible for
mediating some of the ECM production characteristics of
the 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 an
in vitro serum-free coculture system. It revealed that there
was a considerable increase in proliferation seen in any
fibroblasts cocultured with KKs, as compared with NK
controls.56 This strongly suggests that KKs might have an
important role in keloid pathogenesis by producing signals
that stimulate the fibroblasts in the underlying dermis to
proliferate or produce more ECM.56
Additionally, because it is well-documented that KFs
have 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 in
coculture with fibroblasts expressed more TGF-␤1, -␤3,
and TGF-␤ receptor than NKs. KFs cocultured with KKs
expressed more mRNA for TGF-␤1, -␤3, and TGF-␤1
receptor and Smad2 than NFs. Finally, KFs produced more
collagen 1, CTGF, and IGF-1 receptor when cocultured
with KKs compared with NKs.62 A more recent study re-
vealed that KKs produced more TGF-␤2 mRNA than
NKs, in response to serum stimulation.63
Combining these data suggests that keloid pathogenesis
likely results from an exaggerated response to cellular stress
and abnormal keratinocyte-fibroblast signaling, which
promotes this abnormal scar formation.62,63 Other data
have suggested that the leading edge of the keloid is differ-
ent from the center where the process has already burned
out. This is reflected in the finding that there is an increased
inflammatory 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 Because
there remains a lack of a successful animal model for keloid
formation, the development of a model to allow additional
Vol. 206, No. 4, April 2008
investigation of these interactions would be extremely ben-
eficial in deciphering the pathogenesis.
CURRENT THERAPIES AND
FUTURE PROSPECTS
Unfortunately, a single effective therapeutic regimen has
yet to be established for treatment of keloids. Prevention is
an obvious answer, but it is not possible to forego vital
operations because of a potential risk of keloids. Although
there is no single definitive treatment modality, there are
numerous 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 4
provides a synopsis of these various regimens to review the
actual scientifically based evidence and to provide some
insight into the options that are truly advantageous and
appropriate for keloid treatment.
Both silicone and non-silicone–based occlusive dress-
ings have been a widely used clinical option for keloids for
the last 30 years.65,66 Results from several studies have re-
vealed 79% to 90% improvement in keloid scars with the
use of these occlusive dressing, complete resolution has not
been noted.65,66 Pressure dressings have been another non-
invasive treatment modality with wound improvement of
70% to 90%, but once again complete resolution has not
been shown.67 The advantage of both occlusive and pres-
sure dressings is that although they might not completely
eliminate the keloid, they tend to be better tolerated in
pediatric patients and adults who cannot tolerate the other
more invasive therapies.10
Surgical excision alone has been repeatedly proven to be
ineffective, with reported recurrence rates of 55% to
100%.10,68-71 The combination of surgical excision with
other 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 reported
from 8% to 50%.
Various forms of radiotherapy have been attempted as a
monotherapy for keloids, but remain quite controversial
because of anecdotal reports of carcinogenesis after treat-
ment.10,82 As mentioned earlier, radiotherapy after surgical
excision 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, but
none of them have proven to be efficacious. All three forms
Butler et al Progress in Keloid Research and Treatment 735
of laser therapy, according to multiple studies, have recur-
rence rates of upwards of 90%, showing little to no
benefit.83-85
Despite its side effects of pain at the therapeutic site and
hypo- or hyperpigmentation, cryotherapy as a mono-
therapy has proven to be quite effective, with one study
revealing that 73% of patients had substantial flattening of
their keloid scars.86 Additionally, of those scars that did
respond, there were no recurrences reported. Cryotherapy
combined with corticosteroid injections also had relatively
good results in one study, where 67% of patients had sub-
stantial scar flattening and, once again, no recurrence of
those scars that responded.87
Intralesional triamcinolone acetone injections, a type of
corticosteroid, have been a relatively effective first-line
therapy for the treatment of keloids. Although, their exact
mechanism remains unclear, one study revealed a slightly
less than 50% 5-year recurrence rate when triamcinolone
acetone was used as a monotherapy.72 As mentioned earlier,
it has increased efficacy when combined with both surgical
excision72,73 and cryotherapy87; the need for multiple injec-
tions, along with the side effects of injection pain, skin
atrophy, telangiectasias, and altered pigmentation have
caused clinicians and researchers to continue to look for
other means of treatment.
Several pharmacologic agents have recently emerged as
promising treatments for keloid scars. Only small studies
have taken place, but monotherapy with intralesional
5-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 that
initially responded. There are also reports of several other
medications, when used in conjunction with surgical exci-
sion, giving relatively successful results. Postsurgical in-
tralesional interferon injections,73 intralesional verapamil
injections,90 and topical imiquimod cream91,92 resulted in
54%, 44%, and up to 25% recurrence rates, respectively.
Unfortunately, despite the success that has been seen with
these medications, all of them have been associated with
various side effects, ranging from skin pruritus, to altered
pigmentation, to injection pain. Additionally, the studies
have also been relatively small in scope. It is quite apparent
that additional investigation is imperative to elucidate
those agents that have the absolute best efficacy, to deter-
mine the appropriate dosages and most optimal timing of
administration of those agents, and to ensure the preven-
tion of those agents’ untoward side effects.
It is becoming increasingly obvious that failure of these
treatments just highlights the essential problem in keloids;
there is still no clear molecular mechanism defined for ke-
loid development. Increased understanding at the molecu-
 736
Table 4. Summary of Keloid Treatment Modalities
Modality First author No. of treated keloids Wound improvement Recurrence of keloid (%) Side effects
Silicone occlusive dressing (6-mo Wong65 19 79% had substantial reduction in NA None reported

application)
Nonsilicone occlusive dressing
(8-wk application)
Butler et al
erythema, scar elevation, and
pruritus
Bieley66 21 90% had an average of 35% NA 10% had folliculitis
reduction in scar elevation.
67% had reduced erythema
74% had reduced tenderness

Progress in Keloid Research and Treatment

Pressure dressing (25 mmHg of Robertson67 40 70% had 75–100% reduction in NA None reported
pressure, worn 8–24 h/d) scar elevation
Surgical excision Estes68, Niessen69, ⬎200 NA ⱖ55% (1 y) Pain at surgical site
Slemp70, Berman71
Cryotherapy Rusciani86 65 73% with complete flattening of 0% recurrence after 42 mo Pain on freezing
the scar of the 73% that responded Skin pigment changes
Argon laser (488 nm) Hulsbergen83 45 Transient shrinkage of scar by ⬎90% (1 wk) Hyperpigmentation
⬃20% in 50%
CO2 laser (10,600 nm) Norris84 23 NA ⬎95% (10 mo) None reported
Pulse dye laser (585 nm) (1–3 Paquet85 11 Minimal improvement of NA None reported
sessions) erythema or pruritus
Combined surgical excision and
immediate postop x-ray
therapy
Sallstrom75 124 Subjectively, 92% had excellent 8% (1 y) Slight hyperpigmentation
improvement (31%)
Telangiectasias (15%)
Kovalic76 100 NA 27% (9 y) None reported
Combined surgical excision and
immediate postop single
fraction radiotherapy (10-Gy
given 24 h postop)
Ragoowansi78 80 NA 9% (1 y) Slight hyperpigmentation
16% (5 y)
Meythiaz79 56 NA 10% (1 y) Slight hyperpigmentation
(14%)
Transient pruritus (100%)
Combined surgical excision Escarmant77 855 Symptoms improved in 80% 21% (1 y) Bruising
immediate postop interstitial Good cosmetic result in 75%
radiotherapy (Iridium 192)

J Am Coll Surg
(continued)
 Vol. 206, No. 4, April 2008
Table 4. Continued
Modality First author No. of treated keloids Wound improvement Recurrence of keloid (%) Side effects
Combined surgical excision and Malaker80 47 NA 12.7% (6 mo) Transient Pigment
immediate postop cobalt 60 changes (25%)
teletherapy radiation (1,600 Perichondritis (6.3%)
cGy in 4 equal fractions of 400
cGy for 4 d)
Combined surgical excision and Guix81 147 Good cosmetic result in 88.4% 3.4% (7 y) Skin pigment changes
immediate postop high-dose (5%)
rate brachytherapy (12 Gy in 4 Telangiectasias (7%)
equal fractions of 300 cGy for
24 h)
High-dose-rate brachytherapy Guix81 22 Good cosmetic result in 77% 13.6% (7 y) Skin pigment changes
alone (18 Gy in 6 equal (5%)
fractions of 300 cGy for 24 h) Telangiectasias (7%)
Intralesional corticosteroid Kiil72 37 Initial flattening of scar 30% (1 y) Pain at injection site
injection (triamcinolone 50% (5 y) Skin atrophy at site
acetone) (10–40 mg/mL 6-wk Hypopigmentation
intervals) Telangiectasias
Combined surgical excision and

Butler et al
postop corticosteroid injection
(triamcinolone 10–40 mg/mL,
6-wk intervals)
Kiil72 15 Initial excellent healing 30% (1 y) Pain at surgical/injection
50% (1 y) site
Skin atrophy at site

Progress in Keloid Research and Treatment

Davison73 26 Initial excellent healing 15% (2 y) Pain at surgical/injection
site
Hypopigmentation
Telangiectasias
Combined cryotherapy and Farahnaz87 22 67% had flattening of the scar 0% recurrence after 1 y of Pain at freezing and
corticosteroid injection 49% were asymptomatic after the 67% that initially injection site
(triamcinolone 10–40 mg/mL, treatment responded Skin pigment changes
6-wk intervals for 3 mo)
Combined pulse dye laser and Connell93 10 40% had decreased erythema NA None reported
corticosteroid injection 60% had flattening of the scar
(triamcinolone acetone) (10– 70% had decreased pruritus
40 mg/mL 6-wk intervals)
(continued)

737
 738
Butler et al
Table 4. Continued
Modality First author No. of treated keloids Wound improvement Recurrence of keloid (%) Side effects
5-Flouracil (5-FU) (16, 1-wk Gupta88 24 33% had ⬎75% scar flattening 0% recurrence after 1 y of Pain at injection site
interval, intralesional injection 50% had ⬎50% scar flattening the ⬎80% that initially hyperpigmentation
(50–150 mg) responded Ulceration of scar
Bleomycin tattooing (1.5 IU/mL)

Progress in Keloid Research and Treatment

Espana89 15 46% had 100% scar flattening 15% (1 y) Dermal atrophy
46% had ⬎90% scar flattening Hyperpigmentation
100% had some form of wound
improvement
Farahnaz87 26 88% had reduction in lesion size 0% recurrence of the 88% Skin pigment changes
and scar flattening that initially responded
69% were subjectively
asymptomatic after treatment
Combined surgical excision and Davison73 13 NA 54% (2 y) Skin irritation
postop intralesional interferon- Hyperpigmentation
␣2b injection Pain
Skin sloughing
Combined surgical excision and D’Andrea90 22 NA 44% (18 mo) (but 36% of Pruritus
postop intralesional Verapamil these had smaller keloids
hydrochloride injection than before tx)
Combined surgical excision and
postop imiquimod 5% cream
wound application (daily for
8 wk)
Martin-Garcia91 8 NA 25% (6 mo) Hyperpigmentation
Skin irritation at site
Stashower92 8 NA 0% (4 mo) Transient pruritus and
pain that resolved upon
completion of tx
Combined surgical excision, Jackson74 7 NA 42% (5 y) Pain at surgical site
postop single corticosteroid
injection (triamcinolone 40
mg/mL) and pressure earring
worn for 1 y
tx, treatment; NA, not applicable or addressed; postop, postoperative.

J Am Coll Surg
Vol. 206, No. 4, April 2008
lar level will lead to development of new therapies. Deter-
mining how to control profibrotic growth factors,
obtaining a better understanding of the immune response
to injury and the wound healing process, and developing a
model system to better understand the interactions in-
volved in keloid biology will provide insight for the estab-
lishment of more effective therapeutic options for these
patients.
Author Contributions
Study conception and design: Butler, Longaker, Yang
Acquisition of data: Butler, Longaker, Yang
Analysis and interpretation of data: Butler, Longaker, Yang
Drafting of manuscript: Butler, Longaker, Yang
Critical revision: Butler, Longaker, Yang
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