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
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
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
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.
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
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.
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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.
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5. Kelly PA. Medical and surgical therapies for keloids. Dermatol Ther. 2004;17:212-218.
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11. Chen MA, Davidson TM. Scar management: prevention and treatment strategies. Curr Opin Otolaryngol Head Neck Surg. 2005;13:242-247.
12. Alster TS, Tanzi EL. Hypertrophic scars and keloids: etiology and management. Am J Clin Dermatol. 2003;4:235-243.
13. Granstein RD, Rook A, Flotte TJ, et al. A controlled trial of intralesional recombinant interferon-gamma in the treatment of keloidal scarring. Clinical and histologic findings. Arch Dermatol. 1990;126:1295-1302.
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.
15. Al-Attar A, Mess S, Thomassen JM, et al. Keloid pathogenesis and treatment. Plast Reconstr Surg. 2006;117:286-300.
16. Asilian A, Darougheh A, Shariati F. New combination of triamcinolone, 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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