INTRODUCTION
Keloids and hypertrophic scars are formed from the excessive proliferation of
collagen in lesions, which accidents, insect bites, burns, vaccinations, use
of
piercing jewelry, acne and infections, with an exaggerated recruitment of
fibroblasts and excessive deposition of extracellular matrix1 can cause. Such injuries
predominate in females, as estrogen is associated with more serious conditions,
and tend to be located in joints and body folds due to the constant distension
of these locations during daily body movements2.
Regarding its epidemiology, it can be stated that these lesions are more frequent
in darker skin tones. Hochman et al.3 indicated Fitzpatrick phototype III as the most common among
patients with fibroproliferative scars. Furthermore, in people aged 25 years
or
older, the majority of injuries are traumatic in origin4. It is also known that
Caucasians are less susceptible to developing keloids and hypertrophic scars
when compared to African Americans, suggesting that genetic mechanisms may be
involved in the pathogenesis of these lesions5,6.
Although it is known that both constitute an abnormal fibroproliferative response
to the healing process, it is possible to highlight some differences between
them. The keloid invades beyond the original edges of the wound and does not
regress after its formation. The hypertrophic scar, in turn, respects the
previous limits of the injury, forms and regresses in a shorter time, and is
associated with subsequent wound contracture7,8.
The formation process of pathological scars is not fully understood, and some
studies suggest the participation of cells such as fibroblasts, myofibroblasts,
mast cells, and other cytokines such as tumor necrosis factor α and
TGF-β29,10. The
abnormal growth of these scars is enhanced by chronic inflammation in the
reticular dermis, and, generally, the hypertrophic scar presents a loss of this
dermal inflammation, and the keloid develops long-lasting inflammation11. Such inflammation is a
triggering factor for a cascade of interleukins that are deeply involved in the
mechanism of development of these wounds, which can be the target of specific
treatments12.
Therefore, the basis of treatment is based on the pathogenesis of hypertrophic
scars and keloids, and different approaches can be used, such as surgery,
cryotherapy, radiotherapy, intralesional injection (which can be done with
corticosteroids, 5-fluorouracil, and verapamil) and laser therapy13. There is also a subdivision
into non-invasive therapies, such as pressure garments, physiotherapy, silicone
plates, and onion extract14.
Different approaches can be indicated according to some criteria, such as wound
healing time, functional deficit, size, presence and amount of adjacent tissue,
and presence of vascularized muscle or fascia beneath the tissue15. Treating these injuries, in
addition to the aesthetic issue, can improve the patient’s quality of life, as
such scars are associated with pain, hyperesthesia, and itching, especially when
it comes to keloids16.
OBJECTIVE
In this scenario, the objective was to conduct a descriptive review of the
literature seeking evidence from the last five years in treating keloids and
hypertrophic scars, carefully analyzing the data found in different databases
regarding the approach to these pathologies.
METHOD
This is a descriptive literature review based on the search for accessible
studies, using the PRISMA17
guideline, adopting the following strategy:
1) Preparation of a research question guiding the search strategy; 2) Variety of
sources for locating studies; 3) Definition of inclusion and exclusion criteria;
and 4) Assessment of the methodological quality of the included articles.
The survey of articles was carried out in February 2022, using the databases
PubMed (US National Library of Medicine/National Institute of Health), LILACS
(Latin American and Caribbean Center for Health Sciences Information), Cochrane
Library, SCOPUS, Web of Science and Grey Literature, published between 2018 and
2022. The PICO strategy was used, which represents an acronym for Patient,
Intervention, Comparison, and “Outcomes” (outcome), and the following question
was created advisor: “What is the evidence for treatment for keloids and
hypertrophic scars?”
The descriptors related to the themes investigated were crossed after searching
for synonyms using the tools MeSH (Medical Subject Headings) and DeCS
(Descriptors in Health Sciences); therefore, the descriptors were defined:
(“Cicatrix, Hypertrophic” OR “Cicatrices, Hypertrophic” OR “Hypertrophic
Cicatrices” OR “Hypertrophic Cicatrix” OR “Scars, Hypertrophic” OR “Hypertrophic
Scar” OR “Hypertrophic Scars” OR “Scar, Hypertrophic” OR “Keloid” OR “Keloids”)
AND (“Therapeutics” OR “Therapeutic” OR “Therapy” OR “Therapies” OR “Treatment”
OR “Treatments”).
At this point in the search, broader terms were intentionally used to identify
more productions, preventing any important studies from being excluded from the
survey. After this, the title and abstract were analyzed to select studies that
evaluated the population and intervention of interest. Case reports, case
series, cross-sectional studies, and cohorts were removed as they presented low
evidence. In addition, duplicate articles and studies not written in English,
Spanish, or Portuguese were excluded.
Therefore, concerning eligibility, the articles were read in full, and studies
with a high risk of methodological bias were excluded, using the Risk Of Bias
2
(RoB 2) tool, a revised tool to assess the risk of bias in randomized studies
(Table 1); articles classified as
literature reviews were not included in the results; however, they were used
in
the discussion. The outcomes defined for this research were the effectiveness
of
isolated and combined treatments for keloids and hypertrophic scars.
Table 1 - Risk of bias in studies.
| Author/Year |
D1 |
D2 |
D3 |
D4 |
D5 |
Final |
|
|
| Hietanen et al.,
2019
|
+ |
+ |
+ |
+ |
! |
+ |
+ |
Low risk |
| Hietanen et al., 2020 |
+ |
+ |
+ |
+ |
+ |
+ |
! |
Some Risk |
| Khalid et al.,
2019
|
+ |
+ |
+ |
! |
+ |
+ |
- |
High risk |
| Abedini et al., 2018 |
+ |
+ |
+ |
+ |
+ |
+ |
|
|
| Kim et al.,
2020
|
+ |
! |
+ |
+ |
+ |
! |
D1 |
Randomization
process
|
| Aggarwal et al., 2018 |
+ |
+ |
+ |
+ |
+ |
+ |
D2 |
Deviations from intended interventions |
| Neinaa et al.,
2021
|
+ |
+ |
+ |
! |
+ |
+ |
D3 |
Missing result
data
|
| Hewedy et al., 2022 |
+ |
+ |
+ |
+ |
+ |
+ |
D4 |
Measuring results |
| Rasaii et al.,
2019
|
+ |
+ |
+ |
+ |
+ |
+ |
D5 |
Selection of
results
|
| Khalid et al., 2018 |
+ |
+ |
+ |
! |
+ |
+ |
|
|
| Tawfic et al.,
2020
|
+ |
+ |
+ |
+ |
+ |
+ |
|
|
| Ismail et al., 2021 |
+ |
+ |
+ |
+ |
+ |
+ |
|
|
| Hedayatyanfard et
al., 2018
|
+ |
! |
+ |
+ |
+ |
! |
|
|
| Babu et al., 2019 |
+ |
+ |
+ |
+ |
+ |
+ |
|
|
| Güngör et al.,
2020
|
+ |
+ |
+ |
! |
+ |
! |
|
|
Table 1 - Risk of bias in studies.
The tools that showed the effectiveness levels of treatments were the Vancouver
Scar Scale (VSS), Visual Analog Scale (VAS), Verbal Assessment Scale (VRS), and
Patient and Observer Scar Assessment Scale (POSAS) with assessment of the
patient and the responsible professional; in some studies, histopathological
analyzes were carried out on preand post-treatment microstructural changes.
RESULTS
Types of study
Seven hundred forty articles were found in the searched databases, of which
15 were selected, with their interpretation and synthesis. All 15 studies
were randomized controlled trials (Figure 1).
Figure 1 - Article selection flowchart.
Figure 1 - Article selection flowchart.
Furthermore, regarding the treatment modalities of the studies included in
the review, there are surgical options with clinical adjuvant:
• Excision associated with radiotherapy;
• Excision associated with corticosteroids.
Intralesional injectable modalities:
• Triamcinolone Acetonide (TAC);
• 5-Fluorouracil (5-FU);
• Verapamil;
• Hyaluronidase;
• Botulinum Toxin Type A (BTX-A);
• Platelet Rich Plasma (PRP).
Scar coverage options:
• Onion extract gel;
• Silicone plate;
• Losartan ointment
• Laser or shock wave therapies:
• Fractional Co2 laser
• Nd-Yag laser;
• Extracorporeal ShockWave Therapy(ESWT).
TAC vs. 5-FU
The study by Hietanen et al.18 on 50 keloids, treated in 2 equal groups, randomly
divided, with intralesional injections at 3-week intervals, indicated that
treatment efficacy did not differ significantly between the groups treated
with TAC and 5-FU. An experienced plastic surgeon clinically defined keloid
remission as flattening the lesion to the point where no further treatment
or injections were indicated, and the remission rate was 46% in the 5-FU
group and 60% in the TAC group at 6 months of follow-up. In addition to this
analysis concerning the POSAS index, both therapies positively evaluated the
patient and the surgeon.
On another occasion, the same group of researchers analyzed the
histopathological response to this treatment19. The most biologically relevant difference
was in baseline myofibroblast values: the response group had more
myofibroblasts at baseline than non-responders, but the difference was not
statistically significant. However, it was indicated that the loss of
myofibroblasts occurs in the group of keloids that respond to injection
therapies but not in the keloids that do not respond, denoting that the
response to therapy is, in fact, associated with the reduction of
myofibroblasts in these lesions.
In addition, the study by Khalid et al.20 compared the TAC groups (group A=51) with TAC +
5-FU (group B=75) in keloids and hypertrophic scars, with one injection
weekly for 8 weeks. The outcomes were evaluated at 4, 8, and 12 weeks
regarding the average reduction in scar height and lesion recurrence, with a
50% reduction in lesion height as a reference for success.
Of the 108 patients who completed the study, both treatment modalities were
effective; however, the average reduction in scar height in group B (5-FU +
TAC) was markedly better than in group A (TAC), with a lower recurrence rate
at 22-month follow-up. Furthermore, individualizing the analysis concerning
keloids, group B showed 78% treatment efficacy, a statistically significant
result superior to group A; The results related to hypertrophic scar did not
demonstrate a statistically significant difference between the two
groups20.
TAC vs. verapamil
In 50 patients conducted in the study by Abedini et al.21, 21 with two or more
lesions (keloids and/or hypertrophic scars), treated with intralesional
injections of TAC or verapamil, with applications every 3 weeks on up to 6
occasions, aimed -compare therapy using the VSS (Vancouver Scar Scale), a
clinical analysis concerning vascularization, pigmentation and recurrence of
lesions for up to 1 year. There was a significant difference between
therapies; the findings revealed that verapamil was ineffective in reducing
VSS parameters (height, pigmentation, flexibility, and vascularity). In
lesions treated with TAC, the effectiveness of the therapy was observed in
all VSS parameters from week 3 onwards, and the average time of decrease in
height and flexibility parameters was 15 weeks, indicating that verapamil
cannot be considered an alternative adequate and effective treatment to the
detriment of TAC, which has a faster therapeutic response with fewer side
effects.
TAC vs. ESWT
The study by Kim et al.22
compared intralesional TAC injections with Extracorporeal ShockWave Therapy
(ESWT) in 40 patients with keloids, who were allocated into two groups. One
group received isolated intralesional injection of TAC, and the other,
TAC+ESWT. After 12 weeks of starting treatment, it was evident that both
groups showed acceptable improvements in most of the dimensions assessed.
However, such improvements were statistically more significant in the second
group, presenting a greater average percentage reduction in the lesion’s
length, width, and height and a better VSS score than the first (p<0.05).
Furthermore, in the Patient and Investigator Global Assessment, more scores
≥4 were evidenced, indicating good or excellent grades, in the TAC+ESWT
group, without serious adverse events occurring, suggesting that ESWT may be
a new form of adjuvant treatment in keloids.
TAC vs. TAC + hyaluronidase vs. verapamil vs. radio frequency vs. CT +
radiofrequency
In this study carried out by Aggarwal et al.23, 80 patients with keloids completed the
study and were allocated into five therapeutic groups, treated with 1-TAC
alone; 2-Hyaluronidase associated with TAC; 3-Verapamil; 4- Radiofrequency
and 5-TAC combined with radiofrequency. The result of the treatment was
evaluated using the VSS scale. In this scenario, it was evident that the
first, second, and fifth groups obtained similar results regarding scar
removal, in which the clearance rate was 75%, 69%, and 75% effective
treatments for keloids. Therefore, the study suggests that TAC, TAC with
hyaluronidase, and radiofrequency with TAC are equally effective and that
verapamil and radiofrequency alone are not good therapeutic methods for
keloids.
TAC vs. BTX-A vs. PRP
Furthermore, the research carried out by Neinaa et al.24, involving 60
patients with keloids, compared 3 isolated intralesional injection
therapies: Group I: Botulinum Toxin Type A (BTX-A); Group II: Platelet Rich
Plasma (PRP) and Group III: TAC. This randomized clinical trial evaluated
scars, VSS, and VRS before and after treatment without specifying an exact
period. A significant improvement was seen, as well as lower expression of
the pro-fibrotic gene CTGF by immunohistochemistry in groups I and II,
compared to III. There was no significant difference between groups I and
II. Therefore, the study concluded that intralesional injection of BTX-A and
PRP generated better outcomes in keloid treatments when compared to
injection with TAC.
TAC vs. CT + PRP
In another study25, the
therapeutic modalities compared were TAC alone or combined with PRP. A
randomized clinical trial was carried out with 40 patients randomly
distributed into two equal groups (A and B). Both received intralesional TAC
20 mg/ml for 4 sessions, 3 weeks apart. Group A patients received additional
intralesional PRP 1 week after TAC injections. After 3 months of follow-up,
both groups showed significant improvement in the parameters of the VSS and
VRS scales. Furthermore, group A significantly improved height,
pigmentation, flexibility, and general VSS, while group B evolved with a
significant incidence of post-TAC atrophy and hypopigmentation.
TAC vs. TAC + BTX-A
In turn, Rasaii et al.26
compared intralesional injection of TAC with BTX-A in a double-masked
randomized clinical trial. Twenty-three patients with at least 2 keloids
were allocated into 2 groups, with participants in group A receiving only
TAC and those in group B, TAC associated with BTX-A. Each keloid underwent
the designated therapy every four weeks for three sessions, evaluating the
symptoms of pain and itching, using the visual analog scale, the height of
the scars using calipers, and scoring them on the VSS. Both modalities
generated a decrease in height, vascularity, and flexibility scores, with no
significant difference between them. However, group B significantly reduced
pain and itching compared to A. Therefore, bimodal therapy indicated greater
efficacy in the adjuvant setting.
Surgical excision + TAC + 5-FU vs. surgical excision + radiation
Khalid et al.27 carried out
a randomized clinical trial with 60 patients with ear keloids, who were
randomly allocated into 2 groups. Group A received treatment with surgical
excision and intralesional injection of TAC + 5-FU. Group B, in turn, was
treated with surgical excision and radiotherapy. Efficacy in group A was
73.33%, and 43.33% in group B (p=0.01), showing a statistically significant
difference between therapeutic modalities at a 6-month follow-up. Therefore,
it was concluded that excision associated with TAC + 5-FU injection is an
effective modality for treating keloids.
Fractional CO2 laser vs. ND-YAG laser vs. both
A study28 compared Nd-YAG
and fractionated CO2 lasers with each other and combined therapy
2 modalities on clinical, histopathological, and biochemical bases. Thirty
patients with at least 3 pathological scars (keloids or hypertrophic scars)
participated in the study, each scar from the same patient being assigned to
different treatment modalities. Participants underwent 4 sessions, with
intervals of 4-6 weeks between them, and the assessment was carried out
using the VSS and the Observer Scar Assessment Scale (POSAS). Histopathology
quantitatively evaluated the presence of collagen and elastic fibers and
biochemistry, the levels of transforming growth factor β I (TGF-β I) and
TGF-β III through immunoenzymatic assay studies. As an outcome, hypertrophic
scars improved more clearly with fractionated CO2, with keloids
showing no significant difference between therapies. Collagen fibers
substantially improved appearance and pattern, and TGF-β I levels were
considerably reduced, while TGF-β III levels showed an insignificant
increase in all treatment modalities. The therapeutic combination in the
same session did not show substantial additional benefit and presented a
greater side effect profile.
Intralesional botulinum toxin A (IL BTX-A) vs. 5-FU
In this study29, a clinical
comparison was proposed between intralesional botulinum toxin A (IL BTX-A)
and IL 5-fluorouracil (IL 5-FU) in treating keloids in 50 patients.
Twenty-two patients (with 26 keloids) were treated with IL BTX-A monthly for
up to 6 months, and another 22 patients (with 27 keloids) were treated with
IL 5-FU weekly for up to 6 weeks; the remaining 6 patients, each with
multiple keloids, were treated with IL BTX-A for some lesions (8 keloids)
and IL 5-FU for their remaining lesions (8 keloids), the main outcome for
clinical improvement was flattening of the lesions. A significantly better
therapeutic response of keloids was detected after IL BTX-A than IL 5-FU
(p=0.041). IL BTX-A achieved excellent and good flattening of lesions (58.8%
and 20.6%) compared to (31.4% and 17.1%) after IL 5-FU. Therefore, IL BTX-A
proved to be more effective, especially for large keloids, with fewer side
effects than IL 5-FU, less pain, itching, and no hyperpigmentation.
Losartan ointment
Hedayatyanfard et al.30
carried out a study to examine losartan ointment’s clinical effects in
reducing hypertrophic scarring and keloids. A randomized, single-masked
clinical trial was carried out with 37 patients who received 5% losartan or
placebo for the treatment of keloids and hypertrophic scars. Of these, 30
patients completed the study, 20 receiving losartan and 10 placebo, being
evaluated for 6 months according to the VSS regarding the criteria
vascularity, flexibility, pigmentation and height, and pain and itching in
scar tissue. In both hypertrophic scars and keloids, VSS scores were
significantly reduced in the stipulated treatment (p<0.01) and relief of
pain and itching. No recurrence of scars was observed 6 months after using
losartan.
Intense pulsatile light (LIP) vs. silicone gel sheet
In a clinical trial31, 28
patients with 65 hypertrophic scars participated. Each scar was divided into
2 equal parts. Half of the scar was treated with 4 sessions of 29J/cm2 of
LIP at 3 weekly intervals. A silicone gel (SGS) sheet was applied to the
other half and changed at 3-week intervals. The Vancouver Scar Scale was
used to grade both halves of the scar before treatment, at each visit, and 3
weeks after completion of treatment. The results showed that scars treated
with LIP significantly reduced flexibility (p=0.002) and hyperpigmentation
(p=0.0001) compared to scars treated with SGS. Although the percentage
reduction in scar height was greater in the IPL group (15.4% compared to
4.6% in the SGS group), the result was not statistically significant
(p<0.065).
Onion Extract
A 202032 study evaluated the effectiveness of Allium cepa L onion extract,
allantoin, and heparin combined in a topical gel in reducing scars after the
second cesarean section in 120 women who had hypertrophic scars after the
first cesarean section. The groups using gel and the control group were
divided into equal numbers, with topical healing gel postoperatively applied
for 6 months, and the outcome was evaluated according to the VSS. Therefore,
significant reductions were observed in the vascularity, pigmentation, and
VSS height subgroups for those who continued treatment for 24 weeks.
DISCUSSION
The scar development process is complex and requires understanding the molecular
mechanisms that cause its development and recurrences. Multimodal therapies
showed better aesthetic and functional results when correctly indicated.
It can be stated that the decision for therapies used to aesthetically and
functionally improve pathological scars must be individualized, considering the
peculiarities of each case. To facilitate decision-making, there is an attempt
to create algorithms, such as APAS, which systematize the choices for different
therapeutic methods, combining them when necessary. This divides the treatment
into the first assessment, softening of scars; approach with technologies and
injections; and treat pigmentation and skin quality33,34.
In the present study, the most frequently discussed clinical therapy was
intralesional injection, performed with TAC or 5-FU alone or combined with other
measures. In general, combined therapies obtained more significant results
concerning aesthetic and symptomatic aspects than isolated measures, which
aligns with the study of a large literature review from 202135.
Regarding surgical therapies for pathological scar excision, several previous
studies indicate that isolated excision does not generate good results, with
a
recurrence rate greater than 50%36. For this reason, in this review, studies that combined
surgical excision with clinical intralesional injection therapies demonstrated
positive results, reiterating meta-analyses on the topic. In another
meta-analysis that examined the use of TAC after 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 to radiotherapy after excision37,38.
Regarding therapy mediated by fractional CO2 laser, it can be seen in
this study that it was superior to other laser modalities. Correlating with the
literature, it is known that this laser is associated with improving clinical
signs and symptoms of pathological scars, such as color, thickness, and itching
of the lesions. It also acts on the pathophysiology of these injuries,
interfering with the orientation of collagen fibers, promoting results in the
flexibility and height of scars39. Furthermore, laser therapy had fewer side effects and
better aesthetic outcomes when associated with intralesional
triamcinolone40.
Some limitations must be considered. We can observe different outcome assessment
scales: clinical analyses, topographics, and opinions of the patient and the
responsible doctor, among others. Therefore, studies evaluate results in a
heterogeneous way. Therefore, according to the analyzed methodologies, there
are
different follow-up methods in the studies, considering counting the outcome
with different temporalities. Furthermore, a meta-analysis could not be
conducted due to heterogeneity among studies to meet all interest criteria. It
is worth noting that more research is needed to identify additional biochemical,
histological, and genetic mechanisms that drive the development and recurrence
of keloid and hypertrophic scarring.
CONCLUSION
The management of keloids and hypertrophic scars continues to be approached in a
multimodal way, without there being a gold standard of treatment that provides
symptomatic and aesthetic reduction and with consistently low recurrence rates.
However, today, combined clinical and surgical treatments, such as intralesional
injections of 5-fluorouracil or triamcinolone, radiotherapy, and excision of
the
lesion, are more effective than isolated therapies. Therefore, further studies
in this field are needed to standardize the treatment of these injuries, aiming
for better patient outcomes.
1. Universidade do Estado do Pará, Cirurgia
Plástica, Belém, Pará, Brazil
Corresponding author: Vinicius Fialho Teixeira Tv.
Perebebuí, 2623, Marco, Belém, PA, Brazil., Zip code: 66087-662, E-mail:
viniciusfialhoteixeira@gmail.com
