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Int J Dermatol. Author manuscript; available in PMC 2022 June 01.
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Int J Dermatol. 2021 June ; 60(6): 661–671. doi:10.1111/ijd.15159.

Keloids: A Review of Therapeutic Management

Samuel F. Ekstein, B.S.1, Saranya Wyles, M.D., Ph.D.2, Steven Moran, M.D.3,4, Alexander
Meves, M.D., FAAD2
1Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, MN
2Department of Dermatology, Mayo Clinic, Rochester, MN
3Division of Plastic Surgery, Mayo Clinic, Rochester, MN
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4Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN

Abstract
Keloid scar formation arises from a disorganized fibro-proliferative collagen response that extends
beyond the original wound margins due to excessive production of extracellular matrix. Despite
treatment options for keloid scars including medical and surgical therapies such as intralesional
steroid injection and surgical excision, the recurrence rate remains high. Herein we consolidate
recently published narrative reviews, systematic reviews, and meta-analyses to provide an
overview of updated treatment recommendations for keloidal scar formation. PubMed access to
the MEDLINE database was used to investigate updates regarding keloid incidence and treatment.
More than 100 articles were reviewed. Keloid management remains a multimodal approach. There
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continues to be no gold standard of treatment that provides a consistently low recurrence rate;
however the increasing number of available treatments and synergistic combinations of these
treatments (i.e., laser-based devices in combination with intralesional steroids, or 5-fluorouracil in
combination with steroid therapy) is showing favorable results. Future studies could target the
efficacy of novel treatment modalities (i.e., autologous fat grafting or stem cell-based therapies)
for keloid management. This review article provides updated treatment guidelines for keloids and
discusses insight into management to assist patient-focused, evidence-based clinical decision-
making.

Introduction
Keloid, meaning “crab’s claw,” was derived from Greek to describe its characteristic clinical
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presentation.1–3 Historically, the earliest-known keloid scarring was reported around 1700
CE Egypt in the Smith Papyrus.4 The term was first introduced into modern medical
literature in 1814.5 Later that century, a medical textbook published, “In regards to
treatment, we are almost helpless. It is pretty certain to reappear after excision, even though
the incisions be carried far into the healthy skin”.6 Today, despite various treatment options,

Address correspondence to Alexander Meves, M.D., Mayo Clinic, 200 First Street S.W., Rochester, MN 55905,
meves.alexander@mayo.edu, Phone: 507-284-2555.
Disclosures: The authors do not have any conflicts of interest and/or relevant financial relationships relevant to the work presented in
this article.
 Ekstein et al. Page 2

keloid scarring continues to escape the normal process of wound healing and remains
recalcitrant.7,8
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From a clinical perspective, keloids appear as elevated, firm bosselated papules and ill-
defined plaques accompanied by variation in color, including erythematous, violaceous, or
brown pigmentation.9 In contrast to normal and hypertrophic scarring, keloids extend
beyond the borders of original injury and fail to regress.8,9 Given their composition of
haphazardly branched and septal disorganized type I and III collagen bundles, keloids are
often symptomatic with accompanying pain and pruritus.10 Following disruption of skin
integrity resulting from superficial and deep injuries, keloids can form within months to
years later,9 causing cosmetic deformation, functional impairment, psychological distress,
and poor quality of life.10,11 A variety of epidermal to dermal insults are implicated
including iatrogenic surgical incisions, burns, trauma wounds, body piercings, insect bites,
folliculitis, chickenpox, herpes zoster infection, vaccinations, and acne.3 Keloid formation
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has also been observed following facial dermabrasion in patients on isotretinoin therapy.12
Indeed, apart from the hairless tissue of palms and soles, keloid scar distribution occurs
without topographic discrimination, including on the cornea.13

Due to the complexity and mechanical forces at work during the wound healing process, the
exact pathophysiology of keloid formation is still undetermined. Risk factors include
personal or family history of keloids, skin of color ethnic groups, pregnancy, puberty and
skin injuries overlying osteogenic surfaces.14 The incidence of keloid scaring in the
Hispanic and African American population is 4.5 to 16%.15 In African Americans, there is a
significant association between keloid scars, obesity, and hypertension.16,17 In a study
examining systemic medical conditions and keloid formation, obesity was present in 28.57%
of the keloid population as compared to 10.98% for the general population (P < 0.001).17
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Hypertension was present in 44.29% of the keloid population as compared to 15.75% of the
general population (P < 0.001).2

Despite a firm understanding of the risk factors for keloid formation, the lack of animal
models limits investigational studies into the precise mechanism of keloid formation.18 The
wound healing process that leads to tissue repair and regeneration proceeds in four time
sensitive phases: (1) hemostasis, (2) inflammation, (3) proliferation, and (4) remodeling.19
The early phase of wound healing leads to the recruitment of inflammatory cells, epithelial
cells and fibroblasts, which relocate into the wound matrix and contribute to scar
remodeling. Specifically, fibroblasts and myofibroblasts create a collagen-containing
extracellular matrix (ECM) that is in a delicate balance of synthesis and degradation.20 An
imbalance associated with collagen production and ECM degradation therefore contributes
to scar formation.20 A pro-inflammatory microenvironment triggered by dysregulated levels
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of three TGF-β isoforms (TGF-β1, TGF-β2, TGF-β3) and other cytokines secreted by the
type 2 T-helper cell (Th2) immune response (IL-4, IL-5, IL-10, IL-13) has been postulated
to play a role in keloid formation.10,21 Furthermore, increased elastin and fibrillin-1
expression has been noted in scar elasticity.22 Recent studies suggest that keloid fibroblasts
displayed different actin filament stiffness and force generation as compared to normal
fibroblasts, which may delineate keloid extension beyond original wound margin.2,23 Keloid
fibroblasts also produce excess ECM when grown on a stiff substrate,2 partly informing the

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increased risk of keloid formation in high-tension body surfaces, such as chest and upper
back.2
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Despite the fact that keloid formation is classified as a benign dermal growth, it can behave
like a malignant tumor in regards to invasion and hyper-proliferation. In contrast to a keloid,
a hypertrophic scar behaves differently and contains mainly type III collagen arranged
parallel to an epidermal surface. Studies suggest a greater genetic predisposition in keloids
compared to hypertrophic scars.24 Four single-nucleotide polymorphisms (SNPs) across
three loci on chromosome bands 1q41, 3q22.3–23, and 15q21.3 associated with keloid
pathogenesis have been identified, although the mechanisms by which these SNPs contribute
to keloid formation is poorly understood.25 MicroRNA-21 signaling pathways also
contribute to keloid formation.24 Furthermore, epigenetic signaling involving histone
modification, regulatory RNA alterations, and DNA methylation are also implicated in
keloid pathogenesis.26
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Keloidal pathophysiology therefore remains multimodal and complex. There are a wide
range of therapies used in treating keloids with various degrees of success graded by time to
recurrence. Keloid treatment can be classified into medical and surgical interventions as well
as a combination including topical agents, intralesional injections, radiation and laser
therapy.27, 28 Numerous clinical trials have reported the effectiveness of various treatments
on keloid scarring. Yet variability in quality and other limitations render it difficult to
ascertain intra-trial comparison. To date, the gold standard of treatment continues to vary
across academic institutions and independent private practitioners.7 Herein, we consolidate
recently published narrative reviews, systematic reviews, and meta-analyses to provide an
overview of updated treatment recommendations for keloidal scar formation.
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Methods
This review explores current therapies available to treat keloids. The PubMed search engine
was used to access the MEDLINE database in order to search for studies pertaining to
keloids. The following search phrases were used to refine results: “Keloid/drug therapy” OR
“Keloid/therapy” OR “keloid”. The article type was limited to review, publication dates were
limited to January 1, 2016, to January 1, 2019, and species was limited to human. A total of
60 articles were identified with the above search criteria. Screening based on English
language (n=4) and relevance (n=16) excluded 20 articles (Figure 1).

Results
I. Medical Therapies
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Triamcinolone acetonide—Triamcinolone acetonide (TAC; Kenalog), an intralesional

corticosteroid injection, remains the most commonly used, first-line choice treatment for
keloid scarring.29 Corticosteroids affect multiple key pathways in the formation of keloids
by decreasing inflammation during the wound healing process.29 It also suppresses collagen
and glycosaminoglycan synthesis, reduces fibroblast development and augments collagen
degradation.29 This treatment can be used as a monotherapy on a mature keloid or as an
adjuvant to surgical excision or laser therapy. Response to TAC injections varies widely with

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a reported 50% to 100% regression.30 One year post- treatment, the recurrence rate is an
estimated 33%.30 After 5 years, the recurrence rate increases to 50%.30 TAC is injected at a
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dosage of 10 to 40 mg/ml into the mid-dermis every 4 to 6 weeks until the scar has resolved.
29 Side effects include skin atrophy and hypopigmentation.

Triamcinolone acetonide in combination with 5-Fluorouracil—The addition of 5-

fluorouracil (5-FU) to TAC is postulated to lower the side effect profile due to a decreased
dose requirement of each agent. Several studies have reported on this combination treatment,
however, the number of reported cases is low.31 Ren et al. report the effectiveness of
intralesional TAC alone compared to TAC in combination with 5-FU in a systematic review
and meta-analysis.31 While hypertrophic scars were not analyzed separately from keloid
scars, the combination of TAC and 5-FU was more effective than TAC alone. Effectiveness
was measured in terms of patient assessment after treatment (odds ratio (OR), 2.92; 95% CI,
1.63 to 5.22, P<0.001), observer assessment following treatment (OR, 4.03; 95% CI, 1.40 to
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11.61; P<0.01), scar height after treatment (mean differences (MD), −0.14; 95% CI, −0.23 to
–0.05; P<0.01), and erythema score (MD, −0.20; 95% CI, −0.34 to –0.06; P<0.01).31 Data
from Alexandrescu et al. support these findings.32

Mitomycin C—Mitomycin C (MMC), a derivative of Streptomyces caespitosus, is an

antibiotic agent with anti-neoplastic and anti-proliferative activities, which has been used as
a topical agent following keloid surgical excision. By inhibiting DNA, RNA and protein
synthesis, MMC prevents cell division and fibroblast proliferation.27 In a meta-analysis,
Shin and colleagues determined the recurrence rate for topical MMC to be 16.5% (95% CI,
7.9 to 31.1). Treatment consisted of 1 mg/mL MMC applied to the surgical wound for 3–5
minutes every 3 weeks.27 No adverse effects at the 1 mg/mL dose were noted.
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Bleomycin—Bleomycin is a cytotoxic agent that induces sclerosis and is commonly used

in the treatment of various malignancies.33 The first reported use of this intralesional
treatment for keloids was in 1996 and achieved a 47% remission rate.30 Illustrating the
difficulty of assessing treatment efficacy, subsequent studies report widely varying degrees
of recurrence. The lowest recurrence rate noted for this treatment is 0% at a mean duration
of 19 months follow up.34 However, another group reported recurrence rates in a Vietnamese
population of 3.8%, 15.4%, 45.5% and 50% at 6, 12, 15 and 18 months follow-up,
respectively.35 The wide range of recurrence rates based on follow-up time is also seen in
intralesional TAC treatment as discussed previously. In a study comparing intralesional
bleomycin to TAC in patients with Fitzpatrick skin types III to V, both treatments were
comparable with no significant difference in efficacy between the two groups.36 However,
there was a high rate of bleomycin induced hyperpigmentation (71.4%).36 A meta-analysis
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to standardize the efficacy of intralesional bleomycin is warranted.

Imiquimod—Imiquimod 5% cream (Aldara) is a topical immunomodulatory treatment,

which increases expression of tissue necrotic factor alpha (TNF-α), gamma and alpha
interferons (IFN-γ and α), and interleukin 1, 6, 8, 12. It also acts as a Toll-like receptor
(TLR) agonist. A meta-analysis of topical 5% imiquimod cream applied for 6–8 weeks post-

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keloid excision showed that the rate of recurrence was 24.7% (95% CI, 3.2 to 76.4); variable
outcomes were reported.27
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Botulinum A—Use of botulinum toxin-A (BoNT-A) in keloid treatment is based on its

ability to reduce muscle tension and thereby wound tension.37 BoNT-A has been reported to
decrease TGF-β expression, reduce fibroblast proliferation and alter collagen activity during
pathologic scar formation.38 A meta-analysis of treating keloids with BoNT-A remains to be
conducted, however, Schlessinger and colleagues reviewed several small studies that have
been performed to date.39 Efficacy of BoNT-A in keloid treatment is not definitive with
studies showing mixed results.39 Interestingly, a meta-analysis of randomized controlled
trials has been conducted on hypertrophic scars in the maxillofacial area and neck, which
showed a statistically significant difference in scar width, patient satisfaction and visual
analysis scores in the treatment of hypertrophic scars.40 While BoNT-A has been reported to
be effective in hypertrophic scar prevention, its use in keloid treatment remains uncertain.
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Interferons—Immune-response modifiers, interferon alpha and gamma (IFN-α and IFN-

γ), are observed at decreased concentrations in keloids.41 Interferons exert anti-viral, anti-
proliferative and anti-fibrotic properties.42 Indeed, IFN-γ and IFN-α antagonize TGF-β
stimulated collagen metabolism in vitro.43 Treating keloids with intralesional interferon
injections have had varying levels of success with adverse reactions, including systemic flu-
like symptoms, pain at the injection site, edema and erythema reported.42,44 IFN-α−2b did
not demonstrate efficacy in treating keloids.45 Al-Khawajah et al. reported that cases that
withdrew due to local pain (n=7 out of 22 patients) during injection and due to severe
systemic symptoms following the first injection (n=2 out of 22 patients).45 Other studies
demonstrate more favorable results. Berman et al. found that intralesional IFN-α−2b
injections into a keloid resulted in a 41% reduction in area.46 In a larger study (n=124) on
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interferon injections following keloid excision, IFN-α−2b demonstrated a lower recurrence

rate (18.7%) compared to TAC (58.5%) and excision alone (51.2%).47

Onion extract (Allium cepa)—Onion extract (Allium cepa) has been shown to
significantly improve dermal collagen organization in animal model scars.48 Additionally,
the derivative of Allium cepa, quercetin, displays anti-proliferative and anti-histamine
effects.48 The majority of trials to date tested this treatment on non-keloidal scars. In a study
by Wananukul and colleagues, 10% onion extract in silicone derivative gel significantly
decreased the incidence of hypertrophic scar formation from median sternotomy.49 However,
no significant difference in keloid incidence between treatment and placebo groups was
observed.49 The use of onion extract may be better suited for combination therapy. When
intralesional TAC alone was compared to TAC with onion extract to treat keloid and
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hypertrophic scars, the TAC with onion extract group demonstrated a statistically significant
improvement in pain-sensitiveness, pruritus, and elevation at week 20.50 Although, no
significant difference in erythema or induration was seen between treatment groups.50 An
additional study examining keloid and hypertrophic scars compared the following three
treatment arms: onion extract alone, silicone gel sheet alone, and combination onion extract
and silicon sheet.51 While onion extract alone was more effective in improving scar color,

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the silicone gel sheet was more effective in reducing scar height.51 The combination of these
treatments provided the best response.51
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Laser-based devices—Forbat and colleagues reviewed the effectiveness of light-, laser-,

and energy-based devices in the management of keloid scars.28 Laser-based devices can be
divided into ablative and non-ablative categories. Ablative lasers remove the epidermal layer
and include erbium-doped yttrium aluminium garnet (Er: YAG) and carbon dioxide (CO2)
lasers. Non-ablative lasers target the dermis and include potassium titanyl phosphate (KTP),
pulsed dye (PDL) and neodymium-doped yttrium garnet (Nd:YAG) lasers.28,52 For CO2
laser treatments, keloid recurrence was noted between 2 weeks and 3 years post-laser.
Treatment with the Er:YAG laser resulted in a 22% recurrence rate at 8 months post-laser.
Nd:YAG laser exhibited recurrence rates that differed based on keloid site at 6 months post-
laser; 52.9% recurrence for anterior chest, 35.7% recurrence for upper arms and 25% for
scapula keloids. While this data is promising for the use of multiple laser sub-categories,
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additional randomized controlled trials are warranted to determine the effectiveness. Khansa
et al. reported a similar conclusion that laser-based devices produced variable results.53
Higher Fitzpatrick skin types are at a greater risk of adverse effects from laser therapy, and
thus the efficacy of laser-based devices to treat keloids in skin of color ethnic groups is not
widely studied.28 In one study evaluating the 1064 nm Nd:YAG laser on patients with
Fitzpatrick skin types I to VI, post-inflammatory pigmentation changes were not observed.54
The Nd:YAG laser may therefore be an acceptable option for patients with darker skin types
IV to VI.54

Laser-based devices in combination with TAC—Pulsed-dye laser (PDL) is a non-

ablative laser that can attenuate keloidal pain and pruritus53 but is limited in its ability to
decrease scar size. PDL alone appears to downregulate TGF-β1 expression with no impact
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on type I collagen formation.53,55 Therefore, PDL in combination with TAC may provide a
synergistic effect as corticosteroids also contribute to reducing collagen synthesis and
increasing collagen degradation.29,53 Combination of these modalities yielded a 60%
improvement in height, 40% improvement in erythema and 75% improvement in pruritus;
however the sample size was small (n=7).56

Improved results with the CO2 and Nd:YAG lasers in combination with TAC have also been
noted.30 Specifically, Stucker et al. demonstrated that intralesional TAC halts early
recurrences of keloids treated with the CO2 laser.57 Another study using CO2 laser with
intralesional TAC over 6 months noted a significant increase in recurrence of keloids in
patients who did not follow-up regularly for TAC injections.58 Kumar et al. noted an additive
effect of TAC and Nd:YAG laser; keloids that persisted following Nd:YAG laser therapy
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were subsequently treated with intralesional TAC, resulting in complete resolution over 18
months to 5 years of follow-up.59

Cryotherapy—Traditional cryotherapy involves using freeze-thaw cycles to damage scar

tissue. Consequent damage to the surrounding skin surface gave rise to a more targeted
approach of intralesional cryotherapy in which a specialized needle probe freezes the scar
from the inside.60,61 A comprehensive review of eight studies found this approach favorable
in reducing scar volume, pain, and pruritis.62 However, persistent hypopigmentation in

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Fitzpatrick 4–6 skin types was observed and recurrence rates varied widely between 0% to
24%.62
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II. Surgical Therapy

Excision—Excising keloids without secondary intervention generally results in a poor
outcome. Excision alone results in a recurrence rate of greater than 50%.63 While certain
wound closure techniques reduce tension at the wound site, no data supports whether a
specific wound closure technique reduces the likelihood of keloid recurrence. However, a
tensionless closure following excision is considered important in reducing scar hypertrophy
and scar widening.64

III. Combined Medical and Surgical Therapies

Triamcinolone acetonide following excision—A recent meta-analysis reported
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whether triamcinolone intralesional injection following surgical excision prevented the

recurrence of keloids.65 Researchers analyzed 4 studies comprising 254 patients and found
that surgery combined with TAC was not effective in lowering the rate of keloid recurrence
with a pooled risk difference of 0.06 (95% CI, −0.16 to 0.28; P, not significant).65 However,
the location of the keloid may be associated with the success of TAC following excision. Ear
keloids exhibited increased responsiveness to TAC following excision.66 In a meta-analysis
examining the use of TAC following excision of ear keloids, the recurrence rate was 15.4%
(95% CI, 9.4 to 24.1%; P<0.001) proving to have similar efficacy as radiotherapy following
excision.66

5-Fluorouracil following excision—5-Fluorouracil (5-FU) is an anti-neoplastic

pyrimidine analog that has an inhibitory effect on fibroblasts.65 Shin and Kim conducted a
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meta-analysis on whether 5-FU prevents keloid recurrence following surgical excision.65

Following analysis of 2 studies with 107 total patients, keloid recurrence was statistically
lower in patients treated with 5-FU (risk ratio, 0.18; 95% CI, 0.04 to 0.75; P=0.02).65 Most
studies injected 50 to 150 mg of 5-FU to the excision border and wound bed following
keloid removal.65

Radiotherapy following excision—Use of radiotherapy for keloid treatment was first

described in 1906.5 Radiotherapy disrupts the normal wound healing process and can
therefore be administered directly to a mature keloid or following surgical excision to
prevent keloid re-formation. Mankowski and colleagues conducted a meta-analysis
systematic review on radiation-based treatments involving 72 studies and 9048 keloids.63
Their data demonstrated that post-excisional radiotherapy was more effective in preventing
recurrence than radiotherapy alone (22% and 37% recurrence rate, respectively, p=0.005).63
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However, radiation as a monotherapy may be recommended when treating elderly patients

for whom surgical removal may not be a viable option due to location or size. Additionally,
radiotherapy applied to mature keloid has been reported to reduce pain and pruritus.67 In
comparing radiation modalities, post-operative brachytherapy had the lowest recurrence rate
of 15%, compared to a 23% recurrence rate for x-ray and 23% recurrence rate for electron
beam radiation.63 In a separate meta-analysis examining ear keloids, radiotherapy following

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surgical excision proved to be effective with a recurrence rate of 14.0% (95% CI, 9.6 to
19.9%; P < 0.001).66
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Furthermore, several studies have reported that excision followed by radiation is safe and
practical.1,63 The most common side effect reported for radiotherapy treatment was
alterations in skin pigmentation including erythema, transient hyperpigmentation,
hyperpigmentation, hypopigmentation, and unspecified pigmentation changes with a total
occurrence of 32.5%.63 Mankowski and colleagues also found that chest keloids have the
highest recurrence rate.63

Pressure therapy following excision—Pressure therapy involves the use of specialized

garments or devices, such as Zimmer splints or magnets to apply a prolonged state of
pressure to the skin.68,69 It is hypothesized that the added pressure modifies wound tension
and causes localized hypoxia.68,70 A meta-analysis examining trials using pressure garments
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to prevent scar formation in burn patients did not report a difference in global scar
assessment between pressure garment treated scars and non-pressure treated scars.71
However, several observational studies using pressure therapy following surgical excision
for ear keloids demonstrate favorable results with recurrence rate of 6.7% to 10.6%.68,69,72
One trial reported a 0% recurrence rate, however, a corticosteroid injection was combined
with pressure therapy following surgical excision, and the study population was small (n=7).
73

Topical silicone following excision—Silicone for prevention of keloids is a pragmatic

form of at-home treatment. Its exact mechanism of action is yet to be elucidated; however
postulated explanations include decreased skin stretching, occlusion, and hydration.7,74
While early studies of silicone gel sheeting suggested high success rates in treating keloids
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and hypertrophic scars, meta-analyses conclude silicone is not an effective treatment

modality for the prevention of keloids.30,75,76 Hsu and colleagues reviewed the effectiveness
of silicone for prevention of keloid scarring in patients with new wounds by evaluating 10
trials that were designed with a treatment and placebo arm.74 Topical silicone did not
provide a significant difference in the prevention of keloids in patients who have a history of
abnormal scarring.74 Furthermore, Cochrane systematic review analyzing 20 clinical trials
concluded that there is weak evidence supporting the use of silicone gel sheeting as a means
of prevention of abnormal scarring, however improvements in scar color and thickness were
observed.77 Silicone can be applied to the skin in the form of a silicone gel sheet or a topical
silicone gel for 12–24 hours per day with twice daily washing for a minimum of 1 month.78

IV. New therapeutic developments

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Verapamil, a calcium channel blocker, which alters fibroblast gene expression resulting in
reduced collagen synthesis and increased collagenase, has been utilized in keloidal
treatment.4 Studies using intralesional verapamil following surgical excision or alone
reported a wide efficacy range from 1.4 to 48% recurrence.79 Its efficacy has been reported
similar to TAC injections; high-quality trials are needed to define the role of verapamil in
keloid treatment.80

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Ultraviolet A1 (UV-A1) phototherapy in the spectral range of 340–400 nm induces increased

collagenase activity.4 Evidence supports its use for fibrosing disorders, including localized
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scleroderma, lichen sclerosus et atrophicus and graft-versus-host disease.81 Only few studies
to date have tested UV-A1 phototherapy in treating keloids in a total of 6 patients with
mixed results.82–84

Other agents that may have a potential role in keloid treatment include tamoxifen and
calmodulin inhibitors. Tamoxifen citrate is a non-steroidal anti-estrogen that downregulates
TFG-β, fibroblast and collagen expression.85 Similarly, calmodulin inhibitors may also
result in scar degradation and warrant further study.4

Angiotensin-converting enzyme inhibitors (ACEIs) affects wound healing by reducing

collagen synthesis, TGF-β1 expression, and fibroblast proliferation.86 Topical enalapril
significantly reduced the mean size of hypertrophic scars in a double-blinded clinical trial.87
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One case report observed improvement in keloid scarring following oral enalapril.88 Topical
captopril used in a separate case report on a post-burn keloid demonstrated improvement in
the lesion and reduced redness, scaling, and itchiness.89

A new alternative to topical silicone is a combination of silicone oil with hypochlorous acid
(HOCL); it is a gel or spray that can be applied twice daily.90 HOCL has an antimicrobial,
antipruritic and anti-inflammatory role by increasing oxygenation and disrupting biofilm
formation.90 Anecdotal reports suggest that HOCL gel performed better than 100% silicone
gel in the management of keloid and hypertrophic scars.90

Apligraf® is a living, human, bi-layered skin substitute that promotes wound healing.91
FDA approved its use for venous leg ulcers and diabetic foot ulcers.91 The potential of using
neodermal products for restructuring keloids continues to be an area of exploration with few
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case reports available in the literature and a pilot study with a small number of participants.
92

Mammalian target of rapamycin (mTOR) is a potential therapeutic target for keloids.93

Research suggests mTOR plays a role in the regulation of collagen expression and decreases
ECM deposition when inhibited.93 It is therefore postulated targeting mTOR with rapamycin
therapy may block excess fibroproliferation leading to abnormal scarring.94 Indeed,
rapamycin treatment of human fibroblasts in vitro blocks collagen synthesis pathways that
are significantly increased in keloid scarring.94

TGF-β1, TGF-β2 and TGF-β3 isoforms appear to have interrelated roles in keloid
pathogenesis.95 The TGF-β3 isoform in particular has been studied in clinical trials.95
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Intradermal avotermin (recombinant TGF-β3) was administered prophylactically to improve

scarring in three double-blind, placebo-controlled, phase I/II studies.96 However, it appears
the phase 3 clinical trial in 2011 did not accomplish its endpoints leading the company to
conclude avotermin may not provide significant benefit for scar revision.97 Efficacy of
targeting other TGF-β isoforms remains to be further investigated.95

miRNAs (microRNA) are non-coding RNAs that silence genes at the post-transcriptional
level.98 The expression of miRNAs in keloidal fibroblasts are expressed at different

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concentrations compared to normal fibroblasts.99 A growing body of research suggests

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specific miRNAs, such as miRNA-29 and miRNA-21–5p, appear to play key roles in keloid
development providing additional targets for novel therapeutics.100,101

Discussion
Understanding fibro-proliferative process of keloid pathogenesis and achieving scar
resolution through treatment modalities has behooved clinical investigators for decades.
Herein we have categorized treatment options into medical, surgical or combination
therapies. In this review, excision alone was the least effective method of treatment (Table
1). While TAC is a current mainstay of keloid management, it is not effective in lowering the
rate of recurrence when administered following excision.65 However, effectiveness may
depend on the location of the keloid as excision followed by TAC was effective for ear
keloids.66 Anatomical location also influences the responsiveness to laser-based devices and
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pressure therapy. TAC appears to be effective in the management of mature keloids,

however, repeated injections may be needed as the recurrence rate increased 27% from year
1 post-treatment to year 5 post-treatment30.

Chemotherapeutics and immunomodulatory agents, 5-fluorouracil, mitomycin C,

imiquimod, and bleomycin are each effective for keloid management (Table 1). Yet long
term follow-up to 5 years post-treatment is lacking. Mitomycin C may reduce recurrence
rates compared to imiquimod. In the meta-analysis conducted comparing mitomycin C to
imiquimod, mitomycin C proved to have greater efficacy in terms of recurrence rates.27
Furthermore, TAC in combination with 5-fluorouracil was more effective in reducing
hypertrophic and keloid scar recurrence compared to TAC alone.31,32 One mechanism could
involve 5-fluorouracil inhibiting the expression of type I collagen gene that is induced by
Author Manuscript

TGF-β; thereby inhibiting excess collagen synthesis similar to corticosteroids.102

Laser-based devices and forms of radiotherapy have also been effective in the treatment of
keloids (Table 1). Efficacy varied by laser type. CO2 laser is least effective, while the
Er:YAG laser resulted in a 22% keloid recurrence rate.28 The Nd:YAG laser shows varying
results based on keloid location with a recurrence rate ranging from 25% for scapular
keloids to 52.9% for keloids located on the anterior chest.28 Radiotherapy showed promising
results following excision. Recurrence rates varied based on radiation type with electron
beam and x-ray resulting in a 23% recurrence rate and brachytherapy resulting in a 15%
recurrence rate.1,63,67 (Table 1)

Future areas of interest include the use of stem cells in preventing keloid formation. Certain
stem cell types such as mesenchymal stem cells and umbilical cord blood stem cells can
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provide antioxidant effects and reduce inflammation during the wound healing process.103
However, their translation into clinical application continues to be limited due to unresolved
concerns related to safety, potential tumorigenicity and effects on fibroblasts.103 Autologous
fat grafting is another method that is being tested due to the lack of adequate results with the
current treatments available.104 Silva and colleagues reviewed the studies of this treatment
for hypertrophic scars and keloids.104 Due to the limited number of studies and hypertrophic

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 Ekstein et al. Page 11

scars being grouped with keloids, more data is needed to determine the efficacy of this
Author Manuscript

therapy.

Conclusion
As keloid pathogenesis becomes better understood, additional mechanistic targets will be
elucidated paving the way for more effective treatments. Further research into tumor growth
and metastasis may provide further insight into keloid pathogenesis. Similarities between
keloid scar formation, tumor growth, and metastasis have been observed, including over-
expression of collagen triple helix repeat containing-1 (CTHRC1), fibroblast activation
protein alpha (FAP-α), and dipeptidyl peptidase IV (DPPIV).105,106 For now, keloid
management remains a multimodal approach. There continues to be no single treatment
available that provides a consistently low recurrence rate. An increasing number of studies
are examining the combination of existing treatments for a synergistic effect. This includes
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laser-based devices in combination with TAC, and 5-FU in combination with TAC. These
combinations are providing favorable outcomes when compared to monotherapy.

Based on the most recent evidence, brachytherapy following excision provides the lowest
rate of recurrence. For ear keloids, specifically, pressure therapy following excision is the
most efficacious based on observational studies. However, in clinical practice, the patient
and physician may opt to a minimally invasive, cost-effective treatment initially. In these
circumstances, multiple TAC injections may be first line, followed by combination therapies
if adequate results with TAC alone are not achieved. Treatment option may be limited to
physician preference and resources available. Radiotherapy is limited to larger, well-funded
medical establishments. Low cost and minimally invasive TAC injections may explain why
TAC, while less effective than other modalities, is the most common form of treatment
Author Manuscript

today.

There continues to be a need for randomized studies with larger sample sizes and longer
follow-up time. Robust keloid patient registries could help assess additional risk factors,
systemic medical conditions associated with keloid formation and effectiveness of various
treatments. As discoveries in keloid pathogenesis unfold, targeted treatment can be designed
to halt mechanistic checkpoints implicated in this type of scar formation. Keloids continue to
have no gold standard of treatment; however the increasing number of treatments available
and synergistic combinations of these treatments is showing favorable results. Future studies
could target the efficacy of novel treatment modalities and the use of combination therapies
for the management of keloids.

1. The following is true about keloids:

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a. Keloids are benign fibroproliferative skin tumors growing beyond the

site of original dermal injury

b. Keloids are malignant fibroproliferative skin tumors growing beyond

the site of original dermal injury

c. Keloids are benign fibroproliferative skin tumors limited to the site of

original dermal injury with high rates of recurrence

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 Ekstein et al. Page 12

d. Keloids are benign fibroproliferative skin tumors limited to the site of

Author Manuscript

original dermal injury with low rates of recurrence

2. True or false: Given their composition of haphazardly branched and septal

disorganized type I and III collagen bundles, keloids are often symptomatic with
accompanying pain and pruritus.

3. Which of the following is considered to be a risk factor associated with keloids?

a. Personal or family history of keloids

b. Skin of color ethnic groups

c. Pregnancy

d. Puberty
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e. Skin injuries overlying osteogenic surfaces

f. All of the above

4. True or false: Pro-inflammatory microenvironment triggered by excess TGF-β

and elevated production of certain cytokines has been postulated to play a role in
keloid formation.

5. What is the correct order of four time sensitive wound healing phases?

a. (1) Inflammation (2) Hemostasis (3) Proliferation (4) Remodeling

b. (1) Inflammation (2) Hemostasis (3) Remodeling (4) Proliferation

c. (1) Hemostasis (2) Inflammation (3) Proliferation (4) Remodeling

d. (1) Hemostasis (2) Inflammation (3) Remodeling (4) Proliferation

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6. How do corticosteroids (i.e. intralesional triamcinolone) affect keloid formation?

a. Decrease inflammation during would healing process

b. Increases collagen and glycosaminoglycan synthesis

c. Reduces fibroblast development

d. Augments collagen degradation

e. A, C and D are correct

f. A, B and C are correct

7. Which of the following lasers is a potential option for keloid treatment in

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patients with darker skin types (Fitzpatrick IV to VI)?

a. Ablative erbium-doped yttrium aluminium garnet laser (Er:YAG)

b. Ablative yttrium-scandium-gallium-garnet laser (YSGG)

c. Ablative carbon dioxide laser (CO2)

d. Non-ablative neodymium-doped yttrium garnet laser (Nd:YAG)

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 Ekstein et al. Page 13

8. True or false: Excising keloids without secondary intervention generally results

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in a good outcome with minimal recurrence rate.

9. Recent studies have proposed that mesenchymal stem cells and umbilical cord
blood stem cells affect wound healing and reduce scar formation. What is the
proposed mechanism?

a. Reduces antioxidant and anti-inflammatory effects during wound

healing

b. Improves antioxidant and anti-inflammatory effects during wound

healing

c. It is unknown

10. True or false: There continues to be no gold standard of keloid treatment that
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provides a consistently low recurrence rate.

Answers

1. A 6. E

2. True 7. D

3. F 8. False

4. True 9. B

5. C 10. True
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Acknowledgments
Funding: This work was supported by the National Cancer Institute; grant CA215105.

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Figure 1.
Flowchart of study identification in literature review.
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Table 1.

Efficacy of medical and surgical treatments on keloid scars

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Mean Recurrence Mean Follow-up

Category Treatment References
Rate (%) (months)

33 12 Morelli Coppola et al, 2018 30

Triamcinolone acetonide
50 60 Morelli Coppola et al, 2018 30

Er:YAG laser 22 8 Forbat et al, 2017 28

Nd:YAG laser 25 to 52.9 6 Rossi et al, 2013 42

Shin et al, 2017 27

Medical Mitomycin C 16.5 ≥6
Rossi et al, 2013 42

Imiquimod 24.7 ≥6 Shin et al, 2017 27

Morelli Coppola et al, 2018 30

Bleomycin 0 to 50 6 to 19 Saray et al, 2005 34
Hu et al, 2019 35
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Intralesional cryotherapy 0 to 24 6 to 21.5 van Leeuwen et al, 2015 51

Surgical Excision >50 6 to 12 Mankowski et al, 2017 52

Triamcinolone acetonide after

excision
15.4 12 to 35 Shin et al, 2016 54, 55

Brachytherapy after excision 15 14.4 Mankowski et al, 2017 52

Combined (Medical X-ray after excision 23 14.4 Mankowski et al, 2017 52
and Surgical)
Electron beam after excision 23 14.4 Mankowski et al, 2017 52

Pressure therapy after Park et al, 2011 57

6.7 to 10.6 18
excision Park et al, 2013 61

Er:YAG, erbium-doped yttrium aluminium garnet; Nd:YAG, neodymium-doped yttrium garnet

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