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―Review―
Keloids and Hypertrophic Scars Can Now Be Cured Completely:
Recent Progress in Our Understanding of the Pathogenesis of Keloids and
Hypertrophic Scars and the Most Promising Current Therapeutic Strategy
Rei Ogawa1, Satoshi Akaishi1, Shigehiko Kuribayashi2and Tsuguhiro Miyashita2
1Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, Tokyo, Japan
2Department of Radiation Oncology, Nippon Medical School, Tokyo, Japan
Keloids and hypertrophic scars are fibroproliferative disorders of the skin that are caused by abnormal
healing of injured or irritated skin. It is possible that they are both manifestations of the same fibropro-
liferative skin disorder and just differ in terms of the intensity and duration of inflammation. These fea-
tures may in turn be influenced by genetic, systemic, and local risk factors. Genetic factors may include
single nucleotide polymorphisms, while systemic factors may include hypertension, pregnancy, hor-
mones, and cytokines. The most important local factor is tension on the scar. Over the past 10 years,
our understanding of the pathogenesis of keloids and hypertrophic scars has improved markedly. As a
result, these previously intractable scars are now regarded as being treatable. There are many therapeu-
tic options, including surgery, radiation, corticosteroids, 5-fluorouracil, cryotherapy, laser therapy, anti-
allergy agents, anti-inflammatory agents, bleaching creams and make-up therapies. However, at present,
we believe that the following combination of three therapies most reliably achieves a complete cure:
surgery, followed by radiation and the use of steroid tape/plaster.
(J Nippon Med Sch 2016; 83: 46
―
53)
Key words: keloid, hypertrophic scar, radiation, steroid, steroid tape
Introduction
Keloids and hypertrophic scars are fibroproliferative dis-
orders of the skin that are caused by abnormal healing of
injured or irritated skin1. Common causes of injury and
irritation are trauma, burn, surgery, vaccination, skin
piercing, acne, and herpes zoster. The scars are red and
elevated, and have an unappealing appearance. More-
over, they associate with intermittent pain, persistent
itching, and a sensation of contraction. Some keloids can
discharge due to the presence of infected inclusion cysts
that arise because the follicles are obliterated by the
scars. The inflammation in the scars is continuous and lo-
cal, being mainly found in the reticular layer of the der-
mis of the skin2. In this reticular layer, there is also accel-
erated angiogenesis and collagen accumulation. These
features suggest that the cause of keloids and hy-
pertrophic scars is an aberrant wound healing process in
the damaged reticular layer of the dermis. This implies
that more superficial damage would not elicit keloids
and hypertrophic scars. Indeed, a clinical study on hu-
man volunteers showed that cutaneous injury must reach
the reticular layer before it results in inflammatory scar
formation3.
Many classical textbooks consider keloids and hy-
pertrophic scars to be completely different types of scar.
Clinicians define hypertrophic scars as scars that do not
grow beyond the boundaries of the original wound,
whereas keloids are defined as scars that spread into the
surrounding normal skin. By contrast, pathologists make
a histological distinction between keloids and hy-
pertrophic scars on the basis of thick eosinophilic (hya-
linizing) collagen bundles called“keloidal collagen”: these
are present in the former scar type but fewer in the latter.
However, there are many cases in which the scar bears
the growth and histological features of both hypertrophic
scars and keloids4. Indeed, it is possible that hypertrophic
Correspondence to Rei Ogawa, MD, Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, 1
―
1
―
5
Sendagi, Bunkyo-ku, Tokyo 113
―
8603, Japan
E-mail: r.ogawa@nms.ac.jp
Journal Website (http://www.nms.ac.jp/jnms/)
46 J Nippon Med Sch 2016; 83 (2)
scars and keloids are manifestations of the same fibropro-
liferative skin disorder4and just differ in the intensity
and duration of inflammation. These features may in
turn be influenced by genetic, systemic, and local risk
factors2.
Pathogenesis of Keloids and Hypertrophic Scars
A number of genetic, systemic, and local factors that in-
fluence the characteristics and quantity of keloids and
hypertrophic scars have been identified. The genetic
causes of pathological scar development may involve sin-
gle nucleotide polymorphisms (SNPs): a genome-wide
association study5showed that four SNP loci in three
chromosomal regions associate significantly with keloid
development in the Japanese population. Moreover, our
study showed that one SNP associates with the clinical
severity of keloids6. There are probably many other ge-
netic factors that have not yet been identified.
In terms of systemic factors, adolescence and preg-
nancy appear to associate with a higher risk of develop-
ing pathological scars7. It may be that sex hormones such
as estrogens and androgens have vasodilatory effects8
that intensify inflammation, thereby worsening keloids
and hypertrophic scars. This is supported by our unpub-
lished data, which suggest that the incidence of keloids
that are not caused by trauma suddenly increases at
around 10 years of age. This implies that the increases in
sex steroid levels at the start of adolescence, not a higher
likelihood of trauma, are responsible for the greater risk
of pathological scar development in adolescents. More-
over, our recent study showed that hypertension associ-
ates with the development of severe keloids9,10. This asso-
ciation may reflect the fact that hypertension damages
blood vessels, thereby increasing inflammation in scar tis-
sue9,10.
Of the many factors that contribute to pathological scar
development, however, we believe that local mechanical
forces play a particularly important role11
―
13. Several lines
of evidence support this notion. First, keloids commonly
adopt distinct site-specific shapes, namely, the typical
butterfly, crab’s claw, and dumbbell shapes on the shoul-
der, anterior chest, and upper arm, respectively. This, to-
gether with our visual analysis using the finite element
method, suggests that keloids are largely determined by
the direction of the tension that is applied to the skin
around the wound site13. Second, keloids show a marked
preference for particular locations on the body: they usu-
ally occur at sites that are constantly or frequently sub-
jected to tension (such as the anterior chest and scapular
regions) but seldom in areas where stretching/contrac-
tion of the skin is rare (such as the parietal region or an-
terior lower leg). This is true even for patients with mul-
tiple/large keloids. Moreover, keloids are rare on the up-
per eyelid. This reflects the fact that eyelid skin is always
relaxed regardless of whether the eyes are open or
closed. An exception may be earlobe keloids: the contri-
bution of mechanical factors to the development of these
keloids may be minor (although friction from the pillow
and the weight of the keloid itself can increase the risk of
keloid development and progression). The most likely lo-
cal cause of these keloids is the repeated attaching and
detaching of the piercing, which may lead to repeated in-
jury and infection. Both are triggers of inflammation.
At present, physicians cannot (or at least find it very
difficult to) control genetic and systemic factors. How-
ever, they can reduce the mechanical forces around
keloids and hypertrophic scars by using various surgical
techniques (including z-plasties ). Moreover, anti-
inflammatory treatments such as corticosteroids or anti-
angiogenesis agents (which reduce the number of blood
vessels) are viable clinical strategies for the treatment of
these scars.
Prevention of Keloids and Hypertrophic Scars
A burn wound that heals in less than 10 days has a 4%
risk of developing into a hypertrophic scar, whereas a
burn wound that takes 21 days or more to heal has a
70% or greater risk of developing into a hypertrophic
scar14. This means that a deep skin injury that extends to
the reticular layer of dermis needs time to heal; however,
if inflammation continues for a long period, then the risk
of developing a pathological scar increases. Histopa-
thological examination of pathological scars reveals that
the epidermis and papillary layer of the dermis are al-
most normal apart from minor inflammation, but the re-
ticular layer shows strong inflammation with more blood
vessels and greater collagen accumulation2,4. Thus, to pre-
vent the formation of pathological scars, it is essential to
ensure speedy wound healing. Since keloids can arise
from very small injuries or from irritated skin (e.g., acne,
herpes zoster, insect bites, and skin injections), special
care should be taken to ensure fast healing of such small
wounds when treating patients with a history of keloids.
Since stretching wounds can evoke inflammation of the
dermis, wounds should be stabilized as soon as the exu-
date from the wound surface has stopped. The wound
healing of the epidermis and dermis differ completely. In
the case of sutured wounds, the epidermis can regenerate
Keloids and Hypertrophic Scars Can Now Be Cured Completely
J Nippon Med Sch 2016; 83 (2) 47
within 7
―
10 days, leading both the patient and the physi-
cian to believe that the wound has healed completely. In
fact, it may take 3 months before the dermis recovers
more than 90% of its normal strength. Thus, prolonged
external mechanical support using tapes, sheets, and/or
garments is recommended for scar prevention. This is
supported by our study, which showed that silicone gel
sheets reduce the tension on the wound site15.
Silicone tape is better than paper tape as it prevents
the epidermal injury caused by repeated taping16. More-
over, silicone tape keeps the scar surface moist. These
tapes can be kept in place until they detach naturally.
The patient does not need to change the tape after taking
a bath/shower. In our experience, patients generally keep
silicone tape in place for about 1
―
2 weeks. The exception
is in summer: perspiration can reduce tape adherence.
If a patient has a clear history of pathological scars,
then stabilization tapes should be exchanged for steroid
plaster/tape about 1 month after epithelization has oc-
curred. Steroid tape has been used to decrease inflamma-
tion of keloids; this practice is particularly common in Ja-
pan and several other countries17. Flurandrenolide tape
(CordranⓇtape), fludroxycortide tape (DrenisonⓇtape),
and deprodone propionate tape (EclarⓇplaster) are avail-
able worldwide. These steroid tapes/plasters should be
changed every 24
―
48 hours and should be cut so that
they just cover the wound, with minimal attachment (if
any) to healthy skin (unpublished data). Since these tapes
differ in terms of the strength of the steroid, the most ap-
propriate tape/plaster should be selected on a case-by-
case basis.
Treatment of Keloids and Hypertrophic Scars
Over the past 10 years, our understanding of the patho-
genesis of keloids and hypertrophic scars has increased
markedly18. As a result, keloids and hypertrophic scars
are now regarded as treatable diseases. At present, there
are many therapeutic options available, including sur-
gery, radiation, corticosteroids, 5-fluorouracil, cryother-
apy, laser therapy, and make-up therapies. However, at
present, we believe that the most reliable approach is a
combination of three therapies, namely, surgery followed
by radiation and steroid tape/plaster.
A. Surgery
Surgical treatment itself can result in the recurrence of
keloids and hypertrophic scars, which are then often
much bigger than the original lesions. Thus, unless the
scar is a minor hypertrophic scar, the decision to surgi-
cally remove a pathological scar should be made very
carefully. To reduce the risk of recurrence, it is also advis-
able to use particular surgical techniques, namely, subcu-
taneous/fascial tensile reduction sutures, z-plasties, and
local flap transfer.
The usefulness of subcutaneous/fascial tensile reduc-
tion sutures reflects the fact that keloids and hy-
pertrophic scars arise from the dermis12. Dermal sutures
do not effectively reduce tension on the dermis: to
achieve this, we must access much deeper structures,
namely, the superficial and deep fascia, and suture them.
This type of suturing will elevate the wound edges
smoothly while placing minimal tension on the dermis.
In other words, the wound edges naturally attach to
each. Only then should dermal and superficial sutures be
used. It is very important to realize that dermal sutures
on their own cannot reduce the tension on the dermis:
this concept is the key to preventing the formation of
pathological scars after surgery.
Zig-zag sutures, including z-plasties, are good for re-
leasing linear scar contractures and tensions. A major
benefit of z-plasties is that segmented scars mature faster
than long linear scars. In particular, if a scar crosses a
joint, zig-zag incision and suturing significantly reduces
the risk of developing pathological scars.
Various local flaps are also useful for releasing scar
contractures. Moreover, because local flaps expand natu-
rally after surgery, they are not prone to postsurgical con-
tractures. By contrast, skin grafts do not expand, which
means that skin grafting tends to generate secondary
contractures that result in circular pathological scars
around the grafted skin. Thus, flap surgery is better for
keloids. In the past, keloid reconstruction with flaps was
discouraged because it was thought that the donor site
could itself develop keloids. However, such donor-site
keloid development can be prevented by multimodal
therapy, including tension-reduction sutures and radia-
tion therapy. This means that, especially for severe
keloids, flap surgery is a highly suitable approach (Fig.
1).
B. Radiation
As mentioned above, the main problem of surgery for
pathological scars is recurrence. However, recurrence can
be controlled by using ever-improving radiation technol-
ogy. In the past, superficial or orthovoltage X-rays (pho-
tons) were used19,20. However, since the safety and effi-
cacy of radiation therapy have improved markedly in re-
cent years, radiation is now used routinely as a highly ef-
fective postoperative adjuvant therapy. As a result,
keloids can be treated with high dose rate-superficial
R. Ogawa, et al
48 J Nippon Med Sch 2016; 83 (2)
Fig.
1 A severe keloid case (a 63-year-old male) who was treated by flap surgery and postoperative radiation.
a. Preoperative view.
b. Removal of the axillary keloid and the flap design on the dorsum.
c. Flap elevation.
d. Immediately after surgery (recipient site).
e. Immediately after surgery (flap donor site).
f. Design of the second surgery
g. Intraoperative view during the second operation.
h. Immediately after the second operation.
i. 1 year after the second operation.
This patient had severe keloids and diabetes mellitus. His ulcers and keloids were removed twice by surgery and
postoperative radiation was performed. Both donor and recipient sites were irradiated. The movement of his left
shoulder recovered completely after the treatment and none of the keloids recurred. The remaining keloids are
being treated by applying steroid plasters.
e
e
f
f
g
g
h
h
i
i
a
a
b
b
c
c
d
d
brachytherapy (HDR-SB)21,22, as well as electron beam ir-
radiation23
―
25. Depending on the shape of the surgical scar,
an HDR-SB applicator can be used to ensure both the
evenness and appropriate localization of the radiation to
the wound surface.
Our review of the literature revealed that to ensure
maximum efficacy and safety, postoperative radiation for
keloids in adults should involve the application of 10
―
20
Keloids and Hypertrophic Scars Can Now Be Cured Completely
J Nippon Med Sch 2016; 83 (2) 49
Fig.
2 A mild keloid case (a 67-year-old male) who was treated by radiation monotherapy.
a. Pretreatment view.
b. 18 months post-treatment.
This patient had a mild chest wall keloid and was treated by high dose rate-superficial brachy-
therapy. A total of 25 Gy was administrated in five fractions over 5 days. The inflammation re-
solved completely. After 1 year of treatment, both the subjective and objective symptoms had im-
proved dramatically.
a
a
b
b
Gy via daily fractions of 5 Gy26. Use of the linear-
quadratic model to calculate the biologically effective
doses (BEDs) for various radiation regimens for keloid
therapy showed that when the BED exceeds 30 Gy, the
recurrence rate is less than 10%, although α/βratio of
keloid has been considered as 10 but may have other
possibilities. Moreover, the risk of secondary carcinogene-
sis is reduced when the BED is 30 Gy or less. Therefore,
we propose that the maximum dose of postoperative ra-
diation therapy for keloids is a BED of 30 Gy. A BED of
30 Gy can be obtained in several ways: a single fraction
dose of 13 Gy, two fractions of 8 Gy, three fractions of 6
Gy, or four fractions of 5 Gy. In addition, recommended
site-dependent dose protocols for the treatment of keloids
are as follows: 20 Gy in four fractions over 4 days (BED=
30 Gy) for the anterior chest wall, shoulder-scapular re-
gion, and suprapubic region; 10 Gy in two fractions over
2 days for the ear lobe (BED=15 Gy); and 15 Gy in three
fractions over 3 days for other sites (BED=22.5 Gy).
It has been reported that of 10,000 individuals between
18 and 64 years of age who are subjected to whole body
irradiation composed of 1 Gy, 670 (6.7%) will acquire
skin cancer27. In general, skin cancer kills one in 500 pa-
tients. Thus, the mortality rate associated with 1 Gy of
whole body irradiation would be 6.7% × 1/500 =
0.0134%; namely, one in 7,500 people. If this reasoning is
applied to earlobe keloid radiotherapy, where 0.05% of
whole body skin is irradiated with 10 Gy, the incidence
of skin cancer associated with this treatment would be
6.7 × 10 × 0.05/100 = 0.0335%, namely, one in 3,000 peo-
ple. The mortality rate of secondary carcinogenesis of
earlobe keloid treatment would be 0.0335/500 =
0.000067%, namely, one in 1,500,000 people. We believe
that this risk is clinically acceptable if informed consent
is obtained from the patients after they have been ad-
vised of the benefits and side effects of this type of treat-
ment.
We have used primary radiation (radiation monother-
apy) to treat older patients or patients with severe huge
keloids (Fig. 2). The total radiation dose in these cases is
higher than that used for postoperative radiation. In such
cases, it is necessary to apply the radiation carefully to
prevent secondary radiation carcinogenesis. It is also im-
portant to obtain informed consent. However, the risks of
primary radiation therapy should be weighed against its
tremendous benefits: it causes subjective symptoms such
as pain and itching to decrease immediately. Moreover,
over the following year, it causes the color and thickness
of the scars to progressively normalize.
C. Corticosteroid Tapes/Plasters
Corticosteroid injections rapidly reduce the volume of
a scar28. However, the downsides of corticosteroid injec-
tions include pain (caused by the injection itself) and dif-
ficulties associated with contraindications such as preg-
nancy, glaucoma, or Cushing’s disease. In our experience,
to prevent menstrual irregularities, the maximum dose of
R. Ogawa, et al
50 J Nippon Med Sch 2016; 83 (2)
Fig.
3 A mild keloid case (a 9-year-old boy) who was treated by steroid tape.
a. Pretreatment view.
b. After 16 months of treatment.
c. After 26 months of treatment.
This patient had a mild right scapular keloid and was treated by fludroxycortide tape (Drenison® tape). The tape
was placed on the keloid 24 hours a day and was changed daily. The inflammation resolved completely. After 26
months of treatment, both the subjective and objective symptoms of the patient had improved dramatically.
a
a
b
b
c
c
triamcinolone should be 5 mg per session. This is actu-
ally a very small dose compared to the doses used in
other reports. This dose also does not cause hypo-
pigmentation or skin atrophy, and effectively reduces the
thickness of pathological scars if the area to be treated at
each intervention is small. Lidocaine (1%) can be used to
dilute the triamcinolone if used over a wide area. A nar-
row needle (30 Gauge) and warming the solution can
help to reduce the pain associated with the injection.
Moreover, the injection should be placed into the edge
between the scar and normal skin: if the injection is per-
formed in the scar, the thick tissue hampers the infiltra-
tion of the steroid solution. This in turn results in in-
creasing pressure in the wound during the injection,
which causes severe pain. When these tips are used, the
patients can generally tolerate monthly steroid injections
for a few months, even a year. However, this is generally
not long enough to achieve a complete cure. Thus, ster-
oid injections may be less promising than other methods
in terms of curative ability.
This problem can be overcome by using steroid tapes/
plasters. Adults between the ages of 18 and 64 years can
be treated with a combination of steroid injections and
treatment with these tapes/plasters: once the entire thick-
ness of a pathological scar has been reduced by several
steroid injections, this effect can be maintained and aug-
mented by using steroid tapes/plasters that the patients
can apply themselves. Most pediatric and older patients
can be treated by steroid tapes/plaster alone because
they have much thinner skin, which means that the ster-
oids are easily absorbed. This is particularly important in
relation to the pediatric cases because children are more
sensitive to radiation than adults. This reflects the fact
that their cells are actively dividing at a greater rate.
Moreover, because they are young, the effects of
radiation-induced damage may have more time to mani-
fest themselves. Thus, radiation therapy is contraindi-
cated in pediatric patients (less than 18 years of age).
This means that, in most cases, surgery is also not indi-
cated because surgery alone associates with a high rate
of keloid recurrence. Children are also more responsive
to steroid tapes/plasters. Thus, steroid tapes/plasters are
a reasonable first-line therapy for keloids and hy-
pertrophic scars in all children (Fig. 3) as well as for mi-
nor keloids in adults.
Interestingly, in our experience, contact dermatitis
(which is common among adult patients who use tapes)
does not tend to occur in children. This may also reflect
the fact that children have thinner skin through which
the steroid is easily absorbed and/or the smaller sebum
secretion in children.
Follow-up of Keloids and Hypertrophic Scars
It is important that sequentially-treated keloid and hy-
pertrophic scar patients are followed up over the long-
term and that they are appropriately educated about scar
management. If patients develop pathological scars in the
first place, it suggests that they may be particularly
prone to recurrence or the development of new patho-
logical scars in response to minor stimulation. Thus,
Keloids and Hypertrophic Scars Can Now Be Cured Completely
J Nippon Med Sch 2016; 83 (2) 51
these patients should be educated in the self-
management of their wounds. In particular, they should
be encouraged to apply steroid tape/plasters during the
early stages of scar development. This will rapidly re-
duce the inflammation in the scar and improve its ap-
pearance. Moreover, laser therapy, anti-allergy agents in-
cluding tranilast, anti-inflammatory agents, bleaching
creams and make-up therapies can be used case-by-case
basis.
Conclusions
Our impression is that physicians in non-Caucasian so-
cieties often avoid actively treating keloids and, if they
do treat these scars, they tend to prefer using steroid in-
jections as the first-line therapy. However, surgery, radia-
tion, and steroid tape/plaster therapy successfully man-
age keloids and hypertrophic scars, and are increasingly
being used, especially in Japanese populations. Thus,
there is now sufficient evidence on which to base a stan-
dard international algorithm for treating pathological
scars. Treatments are likely to improve significantly as
our knowledge of scar biology increases, higher quality
clinical trials are performed, and new agents are devel-
oped.
Conflict of Interest: The authors declare no conflict of inter-
est.
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(Received,
(Accepted,
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Keloids and Hypertrophic Scars Can Now Be Cured Completely
J Nippon Med Sch 2016; 83 (2) 53
