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US Pharm. 2007;32(4):HS15-HS28.
Cheloid, derived from the Greek word chele
(meaning "crab claw"), refers to the way in which lesions grow laterally from
an original scar into normal tissue. Mancini (1962) and Peacock (1970) defined
this excessive amount of scar tissue as hypertrophic if the scar rises above
skin level and stays within the confines of the original lesion and as keloid
if it rises above skin level but grows beyond the confines of the original
lesion.1-4
Keloids are not harmful or life threatening. They
are easily recognizable from their tough, heaped-up, and irregularly shaped
appearance. They can vary in size from a few millimeters to the size of a
football or larger.4
Keloids typically begin as a small lump at the
site of a skin injury and gradually grow beyond the margins of the original
wound but do not penetrate below the surface. They can occur in any area of
the body that undergoes repeated tension or motion. Symptoms include pain,
burning, itching, and tenderness.1,5
EPIDEMIOLOGY
There is no clear understanding of why keloids form in certain people or
situations and not in others.6 Interestingly, this abnormal
scarring only occurs in humans (5%–15% of wounds) and not in other mammals.
1,6 Keloids and hypertrophic scars develop with the same prevalence in
males and females and usually present between 10 and 30 years of age, with
decreasing frequency later in life.1,6 The cosmetic implications
associated with the disfigurement of keloids are the main reason patients seek
medical intervention for this condition.4 Keloids can occur in
persons of any race, but are more common in highly pigmented people. In the
United States, keloids are five to 15 times more prevalent in
African-Americans than in Caucasians.6 African-American and
Hispanic individuals have a 16% increased risk of keloid formation. Other
darker-skinned people, including Asians, have a similar predilection.
1,4,6,7
PATHOPHYSIOLOGY
Although keloids have been studied extensively, the exact mechanism of both
normal and abnormal scar formation still remains somewhat of a mystery.1
For reasons unknown, the mechanisms that regulate scar tissue formation,
inflammation, proliferation, and maturation become uncontrolled.4,6
The growth curve for hypertrophic scars is anywhere from a year to an
indefinite period of time.6 Risk factors for the development of
keloids include: African-American, Asian, or Hispanic ethnicity; deep skin
wounds, such as those from burns or surgical scars; scars from acne,
vaccinations, or chickenpox; family history; and age between 10 and 30 years.
1,4
There is some indication of a genetic
predisposition to keloids.6 The formation of the keloids seems to
run in families with an autosomal recessive or dominant transmission. An
association has been reported between blood type A and the development of
keloids.
Keloid formation also seems to be related to
changes in the immune system. The incidence of excessive scar formation for
race, sex, and age directly correlates with serum immunoglobulin E levels; and
keloid-afflicted patients exhibit a higher frequency of allergic symptoms
compared with individuals with hypertrophic scars.1 Serum
concentration of immunoglobulins M and G has also been reported to be
increased, whereas serum immuno globulin A has been re ported to be
decreased compared with non– keloid-forming patients. Reports of complement
factor differences also exist in patients with keloids; in particular,
complement factors 3 and 4 have been noted to be abnormal.1 In
patients with keloids, complement factor 3 has been reported to be
significantly higher or significantly lower, whereas complement factor 4 has
been increased.
A hormonal influence has been suggested as well,
because keloids often appear in puberty, resolve after menopause, and enlarge
during pregnancy.1
DIAGNOSTIC PARAMETERS
Physical Examination
At the initial examination, a physical examination should be conducted, and an
evaluation of the patient's symptoms and medical history should be performed.
The patient may be referred to a dermatologist or plastic surgeon who can
confirm the diagnosis and assist in keloid removal.
Histology
A diagnosis of keloids is usually based on both a history consistent with
trauma or irritation to the area and clinical findings; however, because
malignant degeneration of keloids has been reported, obtaining a tissue biopsy
may be necessary to make a definitive diagnosis or to rule out tumor formation
or other hypertrophic skin disorders.4
TREATMENT STRATEGIES
No single therapeutic modality has been determined to be totally effective in
the treatment of keloid scars. The most important strategy to consider in the
management of keloid scar formation is prevention.4-7 Prior to all
surgical procedures, a history of abnormal scar formation or a family history
of keloid scar formation should be taken. In patients with a history of keloid
scars, all nonessential surgery should be avoided, especially at sites of
predilection.5 Some areas of the body are more susceptible to
keloid formation, such as the deltoid region of the upper arm, the upper back,
and the sternum. The earlobes and the back of the neck are also common sites.
1,4-6
In situations in which surgery cannot be avoided,
all attempts to minimize skin tension and secondary infection should be made.
Preoperative radiation therapy to the wound is a useful form of prevention,
when possible. Also, prophylactic antibiotics should be given to treat local
flora, and sterile techniques should be maximized.5
Nonpharmacologic Treatment Modalities
Simple Excision:This modality is a longstanding form of treatment for
hypertrophic scars and keloids.1,6 Surgical excision alone is
usually done to remove keloids that develop along the earlobes. Larger, more
severe lesions may receive a combination of surgery followed by radiation
therapy to control scar formation.5 Although surgery is the current
gold standard of care, recurrence rates with surgery alone range from 45% to
100%.1,6-8 Therefore, surgery to remove keloid scars should be
combined with other treatment modalities.5 When surgery was
combined with intradermal corticosteroids, the recurrence rate in the majority
of studies fell below 50%. In contrast, button compression therapy on earlobes
led to no recurrences, and external radiation following excision, often
combined with other therapies, has been associated with recurrence rates of
less than 10%.
Laser Surgery:Laser therapy is
another technique used in the treatment of hypertrophic scars and keloids.
1 Various types of lasers are available (carbon dioxide, argon,
neodymium:yttrium-aluminum-garnet [Nd:YAG], and pulsed dye), each varying by
the use of a different wavelength of laser light. The argon laser (wavelength,
488 nm) was the first laser used; however, it appears to be effective only in
early keloid formation. The carbon dioxide laser (wavelength, 10,600 nm) is
mainly used to debulk large keloids so they can be treated with other
modalities.5 The Nd:YAG laser (wavelength, 1,065 nm) selectively
inhibits collagen production, and the pulsed-dye laser (PDL; wavelength, 585
nm) is more vascular-specific and is thought to stimulate keloid regression.
1,5,6 Although effective, none have been documented to exceed the
results of surgery and more standard adjuvant therapies. The advantage of
laser therapy is that it allows less tendency to scar compared with scalpel
therapy.1 Laser therapy has been shown to be safe, with minimal
pain; however, several treatment sessions may be required for it to be fully
effective.
Occlusive Dressings:Silicone gel
sheets and occlusive dressings have been used with varied success in the
treatment of keloids. The sheets can be worn for as long as 24 hours a day for
up to one year, with care to avoid contact dermatitis and skin breakdown.1
Silicone does not appear to enter the skin;
therefore, the antikeloid effects appear to be secondary to both occlusion and
hydration.1 Studies have suggested that silicone gel increases the
temperature of the scar, thereby increasing collagenase activity. Increased
pressure, hydration of the stratum corneum, and direct pressure on the wound
may also be modes of action.1
Compression Dressings:Mechanical
compression dressings have long been known to be effective forms of treatment
of keloid scars, especially with ear lobe keloids.1 Compression
devices are usually custom made for the patient and are most effective if worn
24 hours a day.6 Pressure devices include ace bandages, elastic
adhesive bandages, compression wraps, pressure earrings, and tubular support
bandages.5 The patient should start wearing a pressure garment as
soon as reepithelialization occurs and continue wearing it until scar
maturation is evident (8–24 hours a day for the first six months). The minimum
recommended level of pressure is 24 mmHg.1
Radiation: Radiation is utilized as
monotherapy or in combination with surgical excision in order to prevent
keloid recurrence. Success with radiation monotherapy has been unacceptable,
with recurrence rates reaching 100%. Some success has been shown with large
doses of radiation monotherapy; however, this may lead to malignant
transformation 15–30 years later.5 Surgery followed by
radiation has a higher success rate compared with radiation alone.1
Although more promising than the other therapies that are available, radiation
therapy may be associated with carcinogenicity and thus has been a cause for
concern. As a result, many clinicians remain opposed to radiation therapy for
hypertrophic scars and keloids. Therefore, radiation therapy is mainly
reserved for scars that are resistant to other treatment modalities.1
Children should not be irradiated unless this is the only viable option. If
so, the metaphyses should be shielded.1,5 Radiation side effects
include hyperpigmentation, localized pruritus, paresthesias, and pain.1
Cryotherapy: Cryotherapy is the
process of freezing keloids using liquid nitrogen; treatment may flatten the
keloid but often darkens the site of treatment.5 Studies that have
evaluated cryotherapy used a protocol of one to three freeze cycles of 10–30
seconds, with therapy repeated every 20–30 days.4 The most
common adverse effects of treatment are pain and depigmentation.1
The rate of no recurrence with significant flattening of the scar ranges from
51% to 74%. Cryotherapy used in combination with intralesional steroids has an
even greater response rate, with objective success reported in 84% of patients.
1,5,7
Pharmacologic Treatment Modalities
Pharmacologic therapy has been the mainstay of keloid treatment, either as
monotherapy or in combination with other treatments. Various treatments and
the proposed mechanisms by which they affect wound healing and scar formation
are listed in Table 1.9
Corticosteroids: Intralesional
corticosteroids are one of the cornerstones of both treatment and prophylaxis
of keloids and hypertrophic scars, with the primary end points of treatment
being softening and flattening of the keloid and improvement of symptoms.
The most commonly used agent is triamcinolone
acetonide (TAC) at 5–10 mg/mL, either alone or in combination with pressure
therapy, surgery, or cryotherapy, usually administered on a monthly basis.
Initial success rates range from 80% to 90%, but recurrence rates are also
high at about 50%.10 The injection can be diluted with lidocaine to
decrease the pain and discomfort associated with it. The injections should be
made into the deep dermis or subcutaneous fat to decrease the risk of skin
atrophy from leakage of the solution into the surrounding tissues. Adverse
events include pain at injection site, skin atrophy, depigmentation, and
telangiectasias.6,11,12
Interferons: The newest
pharmacotherapeutic modalities studied are intralesional injection of
interferon-alpha, -beta, and -gamma. Interferons reduce fibroblast synthesis
of collagen types I, III, and possibly IV, and they increase collagenase
activity by reducing the steady-state levels of mRNA. In an early study by
Granstein et al., interferon-gamma as monotherapy reduced the size of the
keloid in six of eight patients who were studied.13 Recent larger
studies, however, have not demonstrated this clinical benefit. In a study by
Davison et al., patients receiving interferon alpha-2b injections were
compared with a control group receiving triamcinolone injections at the time
of surgery and one week later.14 The study was terminated early due
to the fact that recurrence occurred in 54% of the interferon alpha-2b group
compared to 15% of the triamcinolone group. Adverse events are common with
interferon administration and include flulike symptoms such as fever,
headache, and myalgia and pain during injection.6,9
Patients may be pretreated prophylactically with
acetaminophen for relief of symptoms.15 Based on the limited
clinical successes and the expense of these medications, they are not
considered to be first- or second-line treatments.
5-Fluorouracil: 5-Fluorouracil
(5-FU) is a pyrimidine analog that has exhibited some success in trials,
usually in combination with intralesional steroid injections, postsurgical
excision, and PDL treatments. In a recent single-blinded study by Asilian et
al., 69 patients were randomly assigned into three groups.16
Patients in group 1 received weekly injections of intralesional TAC (10 mg/mL)
for a total of eight weeks. In group 2, patients received weekly injections of
0.1 mL of TAC (40 mg/mL) added to 0.9 mL of 5-FU (50 mg/mL) for eight weeks.
Patients in group 3 received irradiation by 585-nm flashlamp-pumped PDL (5–7.5
J/cm2) at the first, fourth, and eighth weeks in addition to eight
weekly injections of TAC + 5-FU. Lesions were assessed for erythema, pruritus,
pliability, height, length, and width. Sixty patients completed the study. At
the eight- and 12-week follow-up visits, all groups showed an acceptable
improvement in nearly all measures, but in comparison between groups, these
outcomes were statistically more significant in the TAC + 5-FU and TAC + 5-FU
+ PDL groups (P <.05 for all outcomes). At the end of the study, the
erythema score was significantly lower and itch reduction was statistically
higher in the TAC + 5-FU + PDL groups (P <.05 for both outcomes).
Adverse effects include skin irritation, hyperpigmentation, pain, and tissue
sloughing.9,11,15
Imiquimod: Imiquimod induces immune
pathways to initiate healing locally. It is available as a 5% cream and is
started immediately after surgery and continued once daily for eight weeks.
Two recent small studies have illustrated beneficial results of the use of
this agent after surgical excision. In a pilot study by Stashower, four
patients following debulking excision surgeries were administered imiquimod
cream for six weeks.17 At six and 12 months following treatment,
resolution of the keloids and no evidence of recurrence were observed.
In another open-label pilot study, imiquimod 5%
cream was applied daily to eight earlobes after keloid removal for eight
weeks. Six months after surgery, six (75%) of the earlobes did not exhibit
keloid recurrence.18 Side effects included mild-to-marked
irritation at the site of application and hyperpigmentation.5
Bleomycin: Bleomycin sulfate is an
antineoplastic agent that directly inhibits collagen synthesis in skin
fibroblasts. In a study by Naeini et al., bleomycin tattooing was compared
with cryotherapy combined with intralesional TAC injections in 45 patients
with keloids and hypertrophic scars.19 Patients were treated
on a once monthly regimen for four months. While both treatments were equally
effective in scars less than 100 mm2, bleomycin was significantly
better in larger keloids upward from 100 mm2 (P = 0.03) in
terms of therapeutic response. Another study by Saray and Gulec examined the
impact of bleomycin 0.1 mL (1.5 IU/mL) multiple jet injections on a monthly
basis, on 14 patients who had failed treatment with TAC.20 Scar
height, pliability, and erythema were the primary outcomes. Eleven lesions
(73.3%) showed complete flattening at the end of the study period. The mean
scar height was significantly lower, and the mean scores for scar pliability
and erythema were significantly better at the end of treatment (P
<.001, P <.001, and P <.001, respectively). Side effects
included hyperpigmentation and dermal atrophy.9,20
Miscellaneous Pharmacologic Agents:
Many other agents have been tried in small studies or have been detailed in
case reports within the literature. These agents include tacrolimus,
methotrexate, pentoxifylline, colchicines, calcium channel blockers, and
retinoids. All have exhibited some degree of success in the literature;
however, their clinical use is limited.6,9,12,15
Complementary Medicines: Certain
African and Indian remedies have been studied for the management of keloids
and wound healing. Agents exhibiting activity include silver cluster-leaf bark
(Terminalia sericea); river pumpkin root (Gunnera perpensa);
dhaora (Anogeissus latifolia), a deciduous tree of India containing
leucocyanin and ellagic acids; and flame of the forest (Butea monosperma
), the topical extract of the bark of the tropical evergreen. All show promise
in accelerating and managing the healing process, but further studies are
needed before they can be used clinically.11
The Pharmacist's Role
Prevention strategies are the mainstay of treatment and must be discussed when
counseling patients with keloids.5,7 To help reduce the chances of
forming a keloid, patients should be counseled on avoiding trauma to the skin,
elective cosmetic surgery, and tattoos or piercings and on immediately
attending to cuts or abrasions to minimize scarring.5 No treatment
option can completely erase these scars; therefore, the goal of treatment for
keloid scars is improvement in symptoms and appearance and prevention of
recurrence, not complete eradication of the keloid scars. Patients need to be
educated and counseled on how best to prevent and manage the keloid and should
also be advised that keloids are mostly benign.
References
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scars and keloids: a review. Plast Reconstr Surg. 1999;104:1435-1458.
2. Mancini RE, Quaife JV. Histogenesis of experimentally produced keloids.
J Invest Dermatol. 1962;38:143-148.
3. Peacock EE Jr, Madden JW, Trier WC. Biologic basis for the treatment of
keloids and hypertrophic scars. South Med J. 1970;63:755.
4. English SE, Shenefelt PD. Keloids and hypertrophic scars. Dermatol Surg
. 1999;25:631-638.
5. Kelly PA. Medical and surgical therapies for keloids. Dermatol Ther.
2004;17:212-218.
6. Slemp AE, Kirschner RE. Keloids and scars: a review of keloids and scars,
their pathogenesis, risk factors, and management. Curr Opin Pediatr.
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management. Am J Clin Dermatol. 2003;4:235-243.
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intralesional recombinant interferon-gamma in the treatment of keloidal
scarring. Clinical and histologic findings. Arch Dermatol.
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14. Davison SP, Mess S, Kauffman LC, Al-Attar A. Ineffective treatment of
keloids with interferon alpha-2b. Plast Reconstr Surg. 2006;117:247-252.
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treatment. Plast Reconstr Surg. 2006;117:286-300.
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5-fluorouracil, and pulsed-dye laser for treatment of keloid and hypertrophic
scars. Dermatol Surg. 2006;32:907-915.
17. Stashower ME. Successful treatment of earlobe keloids with imiquimod after
tangential shave excision. Dermatol Surg. 2006;32:380-386.
18. Martin-Garcia RF, Busquets AC. Postsurgical use of imiquimod 5% cream in
the prevention of earlobe keloid recurrences: results of an open-label, pilot
study. Dermatol Surg. 2005;31(11 pt 1):1394-1398.
19. Naeini FF, Najafian J, Ahmadpour K. Bleomycin tattooing as a promising
therapeutic modality in large keloids and hypertrophic scars. Dermatol Surg
. 2006;32:1023-1029.
20. Saray Y, Gulec AT. Treatment of keloids and hypertrophic scars with
dermojet injections of bleomycin: a preliminary study. Int J Dermatol.
2005;44:777-784.
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