Keloids: Pathophysiology and management

David T Robles MD PhD, Erin Moore, Michelle Draznin MD, Daniel Berg MD
Dermatology Online Journal 13 (3): 9

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

danberg@u.washington.edu

Abstract

Keloid formation occurs as a result of abnormal wound healing.

Despite the high prevalence of keloids in the general population,
they remain one of the more challenging dermatologic conditions
to manage. More than a cosmetic nuisance, they are often
symptomatic and can have a significant psychosocial burden for
the patient. Although multiple treatment modalities exist, no single
treatment has proven widely effective. In fact, recurrence following
treatment is generally the norm. Combination therapy is likely the
optimal strategy. In this review, we highlight the clinical features,
pathophysiology and management of keloids.

Figure 1 Figure 2

Figure 3 Figure 4

A keloid may be defined as a benign growth of dense fibrous tissue

developing from an abnormal healing response to a cutaneous
injury, extending beyond the original borders of the wound or
inflammatory response. Clinically, they are firm nodules, which
can be skin colored, hypopigmented, or erythematous secondary to
telangiectasias (Figs. 1-4). The color imparted by the
telangiectasias is often of troubling cosmetic concern for the

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patient. Keloids are frequently symptomatic, with most patients
reporting tenderness or pruritis. Lee et al., evaluated 28 patients
with keloids and found that more than 80 percent of patients
experienced keloid associated pruritus and about half experienced
pain [1]. Many patients are affected both physically and
psychologically and report a severe negative impact on quality of
life [2].

Keloids occur most commonly on the chest, shoulders, upper back,

back of the neck and earlobes [3]. For unknown reasons, keloids
occur more frequently among Blacks, Hispanics and Asians and
less commonly in Caucasians [4, 5]. Female predominance has
been noted but this may, in part, be reflected by the number of ear
lobe keloids secondary to piercing among women [6]. Unusual
cases of massive keloids have been reported following severe burn
injury [7] and at the sites of vaccination [8]. Genital keloids have
been reported to occur subsequent to circumcision or following
trauma [9, 10, 11, 12]. In addition, multiple cases of corneal keloids
following corneal trauma have been described [13]. A history of
keloids or hypertrophic scarring is considered a contraindication
for performing multiple procedures, including LASIK eye surgery
for myopia as well as CO2 laser resurfacing. Notwithstanding, a
small case series of five Caucasian patients with keloids, reported
good results after LASIK surgery with no complications or
abnormal scarring [14].

On histologic examination, keloids are found to have increased

collagen and glycosaminoglycan deposition, both major
components of the extracellular matrix [15]. The collagen in
keloids consists of thickened whorls of hyalinized collagen bundles
in a haphazard array, known as keloidal collagen [16]. This is in
contrast to normal scars where collagen bundles are oriented
parallel to the skin surface.

Pathophysiology

The pathogenesis of keloids is complex and involves both genetic

and environmental factors. It is widely accepted that keloids
develop subsequent to injury or inflammation of the skin, but the
exact pathogenesis is still unknown. Inflammatory skin conditions
such as acne vulgaris, folliculitis, varicella infection, or
vaccinations (particularly BCG vaccination) may induce keloid
formation. Keloids most often occur in the setting of surgical or
non-surgical wound healing (e.g., lacerations and earlobe piercing).
Keloids often develop months after a wound or inflammatory
process, but may develop as far out as a year later [4]. Small needle
sticks such as those during local anesthetic injection seemingly do

2
not evoke keloid formation. However, the occurrence of a keloid or
hypertrophic scar following BCG vaccination is not uncommon
and is likely more to the inflammatory nature of the injection
response rather than the size of the wound. In many cases, patients
may not recall an inciting traumatic event or inflammatory process.
These "spontaneous keloids" are postulated to have occurred in
response to some form of inflammatory process perhaps forgotten
or unrecognized by the patient.

Aberrant expression of various growth factors and their receptors

has been described for keloid-derived fibroblasts. For example,
keloidal fibroblasts have been shown to over express the growth
factors: VEGF, TGF-β1, TGF-β2, CTGF, as well as the PDGF-α
receptor [17, 18]. Recent research has focused on elucidating the
relationship between these over expressed growth factors and
pathologic scarring. The question remains whether these growth
factors cause keloid formation or simply increase in response to the
scarring. TGF-β1 is a well-studied player in the pathogenesis of
abnormal scarring and much research is focused on this pathway. A
recent study by Capaner et al. reported that over expression of
TGF-β1 is an important component in the formation of keloids, but
is not a sufficient as an independent factor, giving credence to the
hypothesis that keloid formation is a multifactorial process [19].
Interestingly, despite widespread up regulation of growth factor
receptors, keloidal fibroblasts have significantly reduced growth
factor requirements in tissue culture [17]. In one study, keloidal
fibroblasts were found to have lower rates of apoptosis, thought to
be related to a down-regulation of apoptosis-related genes [20, 21].

Compared to normal dermal fibroblasts, fibroblasts derived from

keloids exhibit increased production of collagen and matrix
metalloproteinases [22]. Appropriate wound healing involves a
delicate balance of increased collagen production and breakdown
of tissue facilitated by matrix metalloproteinases. Analysis of the
proliferation rate of keloid fibroblasts versus those derived from
hypertrophic scars revealed an increased rate among keloid
fibroblasts [23]. Normal scars seem to have a negative feedback
mechanism, whereby fibroblasts are mobilized to repair a
cutaneous defect and their activity is appropriately dampened to
prevent excessive repair. In this regard, fibroblasts derived from
mature scars are capable of suppressing the in-vitro proliferation
that may contribute to pathological scarring [24]. This suggests the
negative feedback mechanism is somehow defective in keloidal
fibroblasts ultimately resulting in exuberant scar formation with the
propensity to recur.

To date, no specific gene has been linked to the development of

keloids. Most cases occur sporadically, although the finding of a
positive family history is not unusual [25]. Marneros and

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colleagues studied fourteen families with multiple affected
members and derived an autosomal dominant with incomplete
penetrance inheritance pattern based on their analysis [26]. Various
polymorphisms of genes encoding TGF-β1, β2, β3 as well as the
TGFβ receptor have been evaluated, but no statistically significant
associations with keloids have been identified [27, 28, 29, 30]. It is
likely that multiple genes impart susceptibility to keloid
development, with different genes contributing to keloid formation
in different families. This would make the identification of specific
genes problematic. Recent advances in genetic technology allowing
for the simultaneous analysis of multiple genes have significantly
contributed to our knowledge of keloid pathogenesis. Satish et al.
reported micro-array data comparing the gene expression profile
from a small number of keloid tissue samples and normal skin. It is
not surprising that they found increased expression of both
fibronectin and the α-1 chain of type 1 collagen proteins that are
commonly associated with abnormal wound healing. Additionally,
several actin isoforms were over expressed in keloid fibroblasts.
Interestingly, there were several apoptosis related genes that
showed elevated expression in keloid fibroblasts, supporting the
idea that disregulation of apoptosis may contribute to keloid
formation. Of note, several tumor-related genes were found to be
up regulated in keloid fibroblasts, with the greatest increase seen in
Ribosomal Protein 18 (RPS18), an important protein for cell
growth [31]. Stat-3, another oncogene involved in cell
proliferation, has also been linked to keloid pathogenesis [32]. It is
clear that analysis of multiple genes through microarray technology
to compare gene expression among keloids and normal scars, holds
promise for understanding the genetic control of keloids [33].

Management

A wide range of therapies exist for keloids, with the most

commonly used modalities being, intralesional steroid injection,
surgical excision, cryotherapy, laser therapy, radiation therapy and
the application of silicon gel sheets. Other treatments that have
been used with variable success rates include, imiquimod, 5-FU,
bleomycin, retinoids, calcium channel blockers, mitomycin C and
interferon-α 2b. It should be noted that the bulk of the evidence for
these modalities is based on smaller studies that employed little or
no placebo control nor blinding of participants or researchers. A
recent meta-analysis of 39 studies, representing 27 different
treatments, reported a 70 percent chance of clinical improvement
with any type of treatment [34]. While this rate is encouraging, the
effect was not statistically significant. Therefore, it is possible that
current treatments may not have any significant effect on clinical
improvement. Based on emerging information on keloid

4
pathophysiology, there is a need for further studies in order to
develop better therapies for pathologic scarring.

Intralesional steroid injection

Intralesional steroid injection is by far the most commonly used

mode of therapy for keloids. Overall, this modality has a high
degree of tolerability as well as effectiveness in reducing
symptoms. Several studies evaluating intralesional steroids have
reported roughly a 50 percent recurrence rate [35, 36, 37, 38, 39].
Triamcinolone acetonide (Kenalog; Bristol-Myers Squibb,
Princeton, NJ) is typically used at a concentration ranging from 10
to 40mg/ml, depending on the size and location of the lesion. For
lesions on the trunk or extremities therapy is usually initiated at
40mg/ml and then titrated accordingly at subsequent visits.
Multiple injections at regular monthly intervals are generally
required for larger keloids. Intralesional steroid injections help
soften and reduce symptoms of pruritus and tenderness. The
complications of intralesional steroid use include, skin atrophy,
hypo- or hyperpigmentation, and the development of
telangiectasias. Because patients typically require multiple needle
sticks, especially for larger lesions, some authors advocate pre-
treatment with topical lidocaine or the addition of lidocaine in the
syringe to help alleviate injection-associated pain [6].
Triamcinolone acetonide has been shown to inhibit collagen
synthesis and fibroblast growth in vitro [40]. It has been reported
that treatment of fibroblasts with triamcinolone acetonide results in
a reduction in TGF-β expression and an increase in bFGF
production. Intralesional steroid injection may be impractical for
very large or multiple keloids, since the pain of injection may be
considerable and there is additional concern due to large doses of
corticosteroids.

Surgical excision

Surgical excision of keloids should be performed with considerable

caution because the rate of recurrence is high [41]. Surgical
excision may be gratifying, providing an immediate cosmetic
correction. However, the excision often leads to a longer scar and
the potential for a larger keloid in the event of recurrence [42].
Adjuvant therapies such as post-excisional steroid injections should
be considered. Some preliminary reports suggest topical
Imiquimod as an adjunct following excision, but long term follow-
up data are lacking. There are also data suggesting the benefit of
topical Mitomycin C as an adjunct to surgical excision, however

5
these are also small studies with short-term followup [43]. A small
case series of four patients reported superior results when collagen-
glycosaminoglycan copolymer neodermis (Integra) was placed at
the time of excision and skin grafting was delayed for several
weeks [44]. The best surgical outcomes are seen with excellent
wound edge closure, combining minimal tension with maximal
eversion and ensuring incisions are made along relaxed skin
tension lines [45]. Patients with a history of keloid or hypertrophic
scar formation should avoid elective surgery or cosmetic
procedures to avoid risk of future keloids [46].

Cryotherapy

Cryotherapy has been used for smaller lesions, but its use is limited
by considerable pain and sometimes prolonged healing following
treatment [6]. Because multiple treatments are often required, the
risk for hypopigmentation in darker-skinned patients is a
significant drawback. Cryotherapy has been reported to alter
collagen synthesis and induce keloidal fibroblast differentiation
towards a more normal phenotype [47]. Some authors advocate the
use of cryotherapy just prior to steroid injection in order to induce
edema and thus facilitate streroid injection [48].

Radiotherapy

Multiple studies utilizing radiation therapy as an adjunct to surgical

excision have been reported, but the lack of a standardized regimen
makes comparisons between studies difficult [49, 50, 51, 52].
Various techniques can be found in the literature, including
superficial x-rays, electron beam, and low- or high-dose rate
brachytherapy [52]. Post-excisional radiotherapy is typically
employed immediately following surgical excision. When
combined with excision, efficacy rates are higher, ranging from 65
to 99 percent [53]. In one retrospective study, single-fraction
radiotherapy within 24 hours of surgical excision was associated
with an 80 percent recurrence-free success rate at at 5-years
followup [49]. In a separate retrospective study assessing the
efficacy of 15-Gy-electron beam irradiation with more than 18-
months followup, a 77 percent recurrence free success rate was
reported [50].

Side effects of radiation therapy include transient erythema and

hyperpigmentation. The risk of carcinogenesis from radiation
therapy of keloids is likely to be extremely low, especially with
modern techniques. Rare cases in the literature discussing a

6
potential association of malignancy with radiotherapy of keloids
can be found [54, 55] but determining causation is difficult. Given
the uncertainty of the risk, it is recommended by some authors to
limit radiotherapy to those who have failed previous excisional
treatments and to patients 21 years of age or older [49].

Laser treatment

The use of lasers for keloid ablation has been disappointing. The
use of the carbon dioxide and argon lasers has been associated with
recurrence rates as high as 90 percent [42]. The most promising
results have come from the use of the 585nm pulsed dye laser
(PDL) [56, 57]. Use of the pulsed dye laser in combination with
intralesional steroid injection may also help soften the lesions and
enhance the integration of steroid [58]. Work by Kuo and
colleagues showed that flashlamp pulsed-dye laser treatment is
associated with a down-regulation of TGF-β1 and up-regulation of
the metalloproteinase MMP-13, suppression of keloidal fibroblast
proliferation as well as induction of apoptosis [59, 60]. Use of the
Nd:YAG laser as a monotherapy or in conjunction with
intralesional triamcinolone injection has shown some promising
results with a large percentage of patients remaining keloid-free at
follow-up [61].

Silicone Gel Sheeting

Silicone gel dressings are a non-invasive and relatively inexpensive

adjunctive treatment modality for keloids. Recently, an
international expert panel recommended silicone gel sheet therapy
as a first line prophylaxis following surgical excision [41]. When
used after surgical excision, 70-80 percent of keloids and
hypertrophic scars did not recur during followup [62]. The gel
sheets provide an occlusive barrier and seem to soften scars by
increasing hydration and have a significant effect on reducing
erythema, pain and itching [63]. Following surgical excision the
silicone gel sheets are applied as soon as re-epithelialization is
achieved and are worn for at least 12 hours per day [4]. The sheets
last approximately 10-12 days and may be washed and reapplied
[64]. A study comparing the effect of silicone versus non-silicone
gel sheets found that non-silicone gel sheets were equally effective
in reducing scar size, induration and symptoms, suggesting that
occlusion is all that is needed for the effect [63]. However, a recent
Cochrane review evaluating the effect of silicone gel sheeting on
prevention and treatment of keloids concluded that effects are
unclear because of the preponderance of poor quality research.

7
They report that high quality research would benefit both patients
and practitioners in their efforts to combat pathological scarring
[65].

Imiquimod treatment

Imiquimod is a topical immunomodulator which is FDA approved

for the treatment of external genital and perianal warts and most
recently, for the treatment of actinic keratoses. It functions through
the toll-like receptor 7 and is known to upregulate pro-
inflammatory cytokines, including TNF-α is known to reduce
collagen production in fibroblasts and thus, topical Imiquimod has
been studied as an adjunct to surgical therapy [66, 67]. Following
surgical excision, topical imiquimod 5 percent cream was applied
each night to the suture line and surrounding area for a total of 8
weeks [67]. Itching, burning, pain and blisters were the reported
side effects. Although no recurrences were noted, followup was
limited to 24 weeks. In another small and uncontrolled study,
imiquimod therapy following excision of eight earlobe keloids
resulted in a 25 percent recurrence [68]. A similar study, also
looking at the effect of adjunct imiquimod after surgical excision of
earlobe keloids, reported no recurrence in 8/8 keloids treated with
the combination therapy [69]. The caveat in interpreting these
studies is that the follow-up was limited to approximately 6 months
and many keloids recur long after this time point. Keloids may
recur with a median of more than 12 months following treatment,
thus follow up at 6 months could potentially overestimate the
efficacy of treatment. Followup for any keloid intervention should
extend to at least 1 year [70], and perhaps even as long as 2-3 years
[71]. Given the small numbers treated and the lack of long-term
follow up, the overall clinical benefit of imiquimod is still unclear.

5-Fluorouracil

5-Fluorouracil (5-FU) is a pyrimidine analog that is converted

intracellularly to a substrate that causes inhibition of DNA
synthesis by competing with uracil incorporation [72]. The
increased rate of proliferation seen in keloidal fibroblasts suggest
that 5-FU may be effective in limiting keloid growth [73].
However, several studies in the literature suggest that the overall
efficacy is not better than other modalities and significant side
effects such as ulceration and hyperpigmentation make topical 5-
FU less appealing [74, 75, 76]. A major drawback of systemic 5-FU
is its association with anemia, leukopenia and thrombocytopenia.
Thus, even intralesional 5-FU should be avoided in pregnant and

8
lactating females and patients with concurrent infections or bone
marrow suppression [72].

Bleomycin

Bleomycin, a chemotherapeutic agent used in many cancers, also

has several dermatologic uses. Bleomycin has widespread effects at
the cellular level, including blocking the cell cycle, degrading DNA
and RNA, and producing reactive oxygen species. A clinical trial of
13 patients with keloids or hypertrophic scarring showed
significant improvement after treatment with intralesional
bleomycin [77]. Another recent study of 45 patients, compared
bleomycin to a combination of cryotherapy and intralesional
triamcinolone. In this study, a technique termed bleomycin
tattooing was used. Multiple punctures were made in the lesions
and bleomycin was applied topically to the areas. Overall, patients
in the bleomycin group showed significantly greater degree of
flattening than patients treated with cryotherapy and intralesional
triamcinolone, though the therapeutic effect was greatest in keloids
with a volume greater than 100 mm2. Transient hyperpigmentation
was seen in 75 percent of patients in the bleomycin treatment
group, although this faded in the majority of patients by three
months post treatment. Hypopigmentation and telangiectasia were
the most common complications of combination cryotherapy and
triamcinolone. In the three months of follow-up reported, there
were no recurrences [78]. However, as previously stated, this
followup is short given that keloids may recur years after
treatment. These small studies indicate bleomycin may have
therapeutic potential in treating keloids, however there is a need for
larger trials that employ more rigorous methodology.

Interferon α-2b

Interferons are cytokines that modulate the activity of growth

factors and have been shown to have both antiproliferative and
antifibrotic effects [79]. There are data to indicate interferons may
increase collagenase activity and could provide therapeutic
potential for keloids through this mechanism [80]. However,
studies looking at interferon α-2b as a single agent have been
disappointing. Davison et al. recently published results from the
first trial looking at interferon α-2b as an adjunct to surgical
excision. The trial enrolled 50 patients and randomized half to
receive intralesional interferon alpha-2b and half to receive
intralesional triamcinolone. The injections were given immediately
after excision and also one week later at a dosage of million units

9
per centimeter of scar with a maximum of five million units.
Patient follow up occurred at 1 week, 1 month, 6 months and 1
year post surgery. Unfortunately, half of the patients randomized to
the treatment arm dropped out of the study prior to receiving
injections. This was attributed to concern over side effects and the
cost of interferon treatment (around $100 per treatment), which is
usually not covered by insurance and was not funded by the study.
The study was halted early because of a significantly greater rate of
recurrence in the treatment group (54% versus 16%) with the group
concluding that intralesional interferon α-2b is not an effective
treatment as an adjunct to excisional surgery [79].

Prevention

Patients with a previous keloid or a family history of keloids are at

increased risk for developing abnormal scars. These patients should
be counseled against body piercing and should avoid elective
cosmetic procedures with a risk for scarring. As discussed above,
wounds should be closed with minimal tension and the use of
adjunctive measures following surgical excision including the use
of silicone gel sheets may reduce recurrence.

Conclusion

Despite their common occurrence and the multitude of treatment

modalities available, keloids remain a significant challenge for
both the clinician and the patient. The lesions are often
symptomatic and troubling cosmetically, resulting in a significant
negative psychosocial burden for the patient. Intense research is
underway to better understand the pathophysiology of the abnormal
processes leading to keloid formation. This will likely lead to more
specific and effect treatments in the future. For now, our greatest
weapon lies in patient education, combination therapy, and
prevention.

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