- Author: David Jansen, MD, FACS; Chief Editor: Joseph A Molnar, MD, PhD, FACS more...
Definition and Historical Background
A keloid is an abnormal proliferation of scar tissue that forms at the site of cutaneous injury (eg, on the site of a surgical incision or trauma); it does not regress and grows beyond the original margins of the scar. Keloids should not be confused with hypertrophic scars, which are raised scars that do not grow beyond the boundaries of the original wound and may reduce over time. See the image below.
Keloids are benign dermal fibroproliferative tumors with no malignant potential. The first description of abnormal scar formation in the form of keloids was recorded in the Smith papyrus regarding surgical techniques in Egypt around 1700 BC. The term keloid, meaning "crab claw," was first coined by Alibert in 1806, in an attempt to illustrate the way the lesions expand laterally from the original scar into normal tissue. Since that time, physicians have attempted to characterize normal scars, hypertrophic scars, and keloids.[1, 4]
Keloids are found only in humans and occur in 5-15% of wounds. They tend to affect both sexes equally, although a higher incidence exists of women presenting with keloids, possibly secondary to the cosmetic implications associated with the disfigurement. The frequency of keloid occurrence in persons with highly pigmented skin is 15 times higher than in persons with less pigmented skin. The average age at onset is 10-30 years. Persons at the extremes of age rarely develop keloids.
Studies have consistently demonstrated that persons of certain races are more susceptible to keloid scar formation. Individuals with darker pigmentation, black persons, and Asian persons are more likely to develop keloids. In a random sampling of black individuals, as many as 16% have reported developing keloid scars, with an incidence rate of 4.5-16% in the black and Hispanic populations. White persons and albinos are least affected. Alhady's 1969 study found that Chinese individuals were more likely to develop keloids than Indian or Malaysian individuals.
Some evidence supports a relationship between genetic predisposition and an individual's propensity to form keloid scars. Genetic associations for the development of abnormal scars have been found for HLA-B14, HLA-B21, HLA-BW16, HLA-BW35, HLA-DR5, HLA-DQW3, and blood group A.
Regions of the human genome highly correlated with keloid formation in 2 pedigrees with familial keloids have been recently identified. The regions identified were in 2 separate, unrelated locations on the human genome, underscoring the complex and multivariable pathogenesis of this disease.
Keloids are dermal fibrotic lesions that are a variation of the normal wound healing process. They usually occur during the healing of a deep skin wound. Hypertrophic scars and keloids are both included in the spectrum of fibroproliferative disorders. These abnormal scars result from the loss of the control mechanisms that normally regulate the fine balance of tissue repair and regeneration.
The excessive proliferation of normal tissue healing processes results in both hypertrophic scars and keloids. The production of extracellular matrix proteins, collagen, elastin, and proteoglycans presumably is due to a prolonged inflammatory process in the wound. Hypertrophic scars are raised, erythematous, fibrotic lesions that usually remain confined within the borders of the original wound. These scars occur within months of the initial trauma and have a tendency to remain stable or regress with time.
Keloid formation can occur within a year after injury, and keloids enlarge well beyond the original scar margin. The most frequently involved sites of keloids are areas of the body that are constantly subjected to high skin tension. Wounds on the anterior chest, shoulders, flexor surfaces of the extremities (eg, deltoid region), and anterior neck and wounds that cross skin tension lines are more susceptible to abnormal scar formation.
The most important risk factor for the development of abnormal scars such as keloids is a wound healing by secondary intention, especially if healing time is greater than 3 weeks. Wounds subjected to a prolonged inflammation, whether due to a foreign body, infection, burn, or inadequate wound closure, are at risk of abnormal scar formation. Areas of chronic inflammation, such as an earring site or a site of repeated trauma, are also more likely to develop keloids. Occasionally, spontaneous keloids occur without a history of trauma.
After the initial insult to the skin and the formation of a wound clot, the balance between granulation tissue degradation and biosynthesis becomes essential to adequate healing. Extensive studies of the biochemical and cellular composition of keloids compared to mature scar tissue demonstrate significant differences. Keloids have an increased blood vessel density, higher mesenchymal cell density, a thickened epidermal layer, and increased mucinous ground substance. The alpha–smooth muscle actin fibroblasts, myofibroblasts important for contractile situations, are few, if present at all.
The collagen fibrils in keloids are more irregular, abnormally thick, and have unidirectional fibers arranged in a highly stressed orientation. Biochemical differences in collagen content in normal hypertrophic scars and keloids have been examined in numerous studies. Collagenase activity, ie, prolyl hydroxylase, has been found to be 14 times greater in keloids than in both hypertrophic scars and normal scars. Collagen synthesis in keloids is 3 times greater than in hypertrophic scars and 20 times greater than in normal scars. Type III collagen, chondroitin 4-sulfate, and glycosaminoglycan content are higher in keloids than in both hypertrophic and normal scars. Collagen cross-linking is greater in normal scars, while keloids have immature cross-links that do not form normal scar stability.
The increased numbers of fibroblasts, recruited to the site of tissue damage, synthesize an overabundance of fibronectin, and receptor expression is increased in keloids. Mast cell population within keloid scars is also increased, and, subsequently, histamine production increases. See the images below.
A study by Touchi et al indicated that the central portion of keloids is severely ischemic. The investigators found greater expression of hypoxia-induced factor-1α, as well as less vascular density, in the center than on the periphery of these lesions.
Growth factors and cytokines are intimately involved in the cycle of wound healing. Immunohistochemical studies of keloids demonstrate an amplified production of tumor necrosis factor (TNF)–alpha, interferon (INF)–beta, and interleukin-6. Production of INF-alpha, INF-gamma, and TNF-beta is diminished. INF-alpha, INF-beta, and INF-gamma reduce fibroblast synthesis of collagen types I, III, and, possibly, VI. A relationship appears to exist between immunoglobulins and keloid formation; while levels of immunoglobulin G and immunoglobulin M are normal in the serum of patients with keloids, the concentration of immunoglobulin G in the scar tissue is elevated when compared to hypertrophic and normal scar tissue. Note that no animal model exists for experimental investigation of keloids.
When a patient presents with an abnormal scar, differentiating a keloid from a hypertrophic scar is necessary. Most patients who present for treatment are concerned about cosmesis, although some present with complaints of pruritic pain or a burning sensation around the scar. Keloids initially manifest as erythematous lesions devoid of hair follicles and other normal glandular tissue. The consistency can range from soft and doughy to rubbery and hard. Most keloids tend to grow slowly over months to a year, extending past the initial area of injury but rarely into the subcutaneous tissue. Most keloids eventually stop growing and remain stable or even involute slightly.
Keloids have a normal epidermal layer; abundant vasculature; increased mesenchymal density, as manifested by a thickened dermis; and increased inflammatory-cell infiltrate when compared with normal scar tissue. The reticular layer of the dermis consists mainly of collagen and fibroblasts, and injury to this layer is thought to contribute to formation of keloids. Collagen bundles in the dermis of normal skin appear relaxed and in an unordered arrangement; collagen bundles are thicker and more abundant in keloids, yielding acellular, nodelike structures in the deep dermal region. The most consistent histologic distinguishing characteristic of keloids is the presence of large, broad, closely arranged collagen fibers composed of numerous fibrils. In addition to collagen, proteoglycans are another major extracellular matrix (ECM) component deposited in excess amounts in keloid scars.
There are four histologic features that are consistently found in keloid specimens that are deemed pathognomonic for their diagnosis. They are 1) the presence of keloidal hyalinized collagen, 2) a tonguelike advancing edge underneath normal-appearing epidermis and papillary dermis, 3) horizontal cellular fibrous bands in the upper reticular dermis, and 4) prominent fascialike fibrous bands.
No single therapeutic modality has been determined experimentally to be most effective for treating keloid scars. The most important thing to consider in the management of keloid scar formation is prevention. Prior to all surgical procedures, thoroughly discuss a history of abnormal scar formation or a family history of keloid scar formation with the patient. In a patient with a history of keloid scars, all nonessential surgery should be avoided, especially at sites of predilection. Persons with only earlobe keloids should not be considered keloid formers. In situations in which surgery cannot be avoided, make all attempts to minimize skin tension and secondary infection. When possible, preoperative radiation therapy to the wound is a useful form of prevention. Also, antibiotics should be given to cover local flora, and sterile technique should be maximized.
Silicone gel sheets and silicone occlusive dressings have been used with varied success in the treatment of keloids. The sheets can be worn for as long as 24 h/d for up to 1 year, with care to avoid contact dermatitis and skin breakdown. The silicone does not appear to enter the skin; therefore, the antikeloid effects appear to be secondary to both occlusion and hydration. Studies have demonstrated that silicone gel increases the temperature of the scar, possibly increasing collagenase activity. Increased pressure, hydration of the stratum corneum, and direct pressure on the wound also may be modes of action. In some studies, the response rate has been as high as 79%, showing substantial reduction in erythema, scar elevation, and pruritus. However, complete resolution has not been noted.
Mechanical compression dressings have long been known to be effective forms of treatment of keloid scars, especially with ear lobe keloids. Compression devices are usually custom-made for the patient and are most effective if worn 24 h/d. Pressure devices include garments made of Dacron spandex bobbinet fabric, shaped Tubigrip support bandages, or zinc oxide adhesive plaster. The patient should start wearing the pressure garment as soon as re-epithelization occurs and continue wearing it until scar maturation is evident. The recommended level of pressure is 25 mm Hg, but good results have been observed with pressures as low as 5-15 mm Hg.
The mechanism of action is unknown; however, by reducing the oxygen tension in the wound through occlusion of small vessels, subsequent reductions in tissue metabolism, fibroblast proliferation, and collagen synthesis result. Studies have demonstrated that with button compression devices on the earlobe, no recurrence was noted from 8 months to 4 years.
Pharmacological therapy has long been a mainstay and relatively effective first-line therapy of treatment of keloids, either as sole treatment or in combination with other therapies. Intralesional steroid injections apparently act by diminishing collagen synthesis, decreasing mucinous ground substance, and inhibiting collagenase inhibitors that prevent the degradation of collagen, thus significantly decreasing dermal thickening. This is accomplished by uniform injection of 10-40 mg/mL of triamcinolone acetonide (Kenalog) into the fresh site of scar excision with a 25- to 27-gauge needle at 4- to 6-week intervals until the scar flattens and discomfort is controlled. The steroid should be injected into the papillary dermis (where collagenase is produced). Avoid injection into the subcutaneous tissues, which causes fat atrophy and undercuts the intended purpose.
Studies examining the effects of corticosteroid injections alone show a 5-year response rate of 50-100% and recurrence rates of 9-50%. When surgical excision is combined with steroid injection, the response rate increases to 85-100%. A typical treatment program of surgery combined with steroids involves injecting Kenalog into the wound edges after excision and repeating injections into the scar at 6-week intervals for a total of 6 months.
Adverse effects of corticosteroid injections include atrophy of the skin or subcutaneous tissue, hypopigmentation, telangiectasia, necrosis ulceration, visible deposition of steroid in the form of white flecks in the scar, and systemic effects resulting in cushingoid habitus. Most of these adverse effects can be avoided by confining injections of the lowest possible dose of steroid to the dermal layer.
Simple excisional surgery should involve the least amount of soft tissue handling to minimize trauma; also, plan the closure with minimal skin tension along relaxed skin tension lines. In an effort to reduce wound tension, both full- and split-thickness skin grafts have been used, but these have been only partially successful. Make all attempts to remove any source of postoperative inflammation, such as trapped hair follicles, foreign material, hematomas, or infectious areas. See the images below.
Recurrence rates with surgery alone range from 45-100%. The combination of surgical excision with other modalities, such as corticosteroid injection, steroid injection with pressure dressing, x-ray therapy, interstitial radiation, single fraction radiation, teletherapy radiation, and brachytherapy have revealed relatively good results, with 5-year recurrence rates reported from 8-50%.[11, 12, 13, 14, 15, 16] See the images below.
Radiation can be used as monotherapy or in combination with surgical excision in order to prevent recurrence. Success with monotherapy has not been acceptable, with recurrence rates reaching 100%. Some success has been shown with large doses of monotherapy; however, this may lead to malignant transformation 15-30 years later. Thus, large-dose monotherapy has fallen out of favor.
The most effective time to give radiation therapy is during the first 2 weeks after excision, while fibroblasts are proliferating. A typical regimen is 300 Gy every other day for 4 days or 500 Gy every day for 3 days, starting the day of surgery. Postoperative radiation is just as effective as combination preoperative and postoperative radiation.
Children should not be irradiated unless this is the only viable option. If so, the metaphyses should be shielded. A case of medullary carcinoma of the thyroid was reported in an 8-year-old boy after excision and postoperative radiation.
Some studies have shown that high-dose brachytherapy combined with surgical excision can achieve good to excellent cosmetic results with an 80-94% prevention of recurrence. However, some residual hyperpigmentation (5%) and telangiectasias (7%) can occur.
A study of postexcision brachytherapy found that keloid recurrence rates were similar with low-dose-rate and high-dose-rate brachytherapy but that the incidence of symptom relief was greater in patients who received high-dose-rate treatment. In the study, the recurrence rates for low-dose-rate (38 patients, 46 keloids) and high-dose-rate (39 patients, 50 keloids) therapy were 30.4% and 38%, respectively. Symptoms of pain, itching, or stress, present at diagnosis in 64 keloids, were relieved in 92% of patients who received high-dose-rate brachytherapy but in just 68% of those who underwent the low-dose-rate treatment.
Cryotherapy uses liquid nitrogen to cause cell damage and to affect the microvasculature, causing subsequent stasis, thrombosis, and transudation of fluid, which result in cell anoxia. Studies that have evaluated cryotherapy used a protocol of 1-3 freeze cycles lasting from 10-30 seconds, repeating the therapy every 20-30 days. The most common adverse effects of treatment are pain and depigmentation. The therapy was quite effective, as the rate of no recurrence with significant flattening of the scar ranges from 51-74%. Cryotherapy used in combination with intralesional steroids has an even greater response rate, with objective success reported in 84% of patients.
A randomized study by Mourad et al indicated that keloid therapy with intralesional cryotherapy is more effective and requires fewer treatments than the spray variety. The study included 50 patients, with a 6-month follow-up.
The advantage of laser therapy is that it is a precise, hemostatic excision with minimal tissue trauma, thereby eliminating an excessive inflammatory reaction. The different modes of laser therapy are flash lamp pulse-dyed laser, carbon dioxide laser, argon laser, and the Nd:YAG laser. The carbon dioxide laser and argon laser work by similar mechanisms (ie, by inducing collagen shrinkage through the laser heat). The pulse-dyed laser induces microvascular thrombosis, and the Nd:YAG laser appears to selectively inhibit collagen metabolism and production. Many studies have been done with these types of lasers over the past 40 years, but none of them have proven to be efficacious. All 3 forms of laser therapy, according to multiple studies, have recurrence rates upward of 90%.[11, 19, 20, 21, 22]
One of the newest therapeutic modalities is intralesional injection of INF-alpha, INF-beta, and INF-gamma. Numerous studies have demonstrated that these interferons reduce fibroblast synthesis of collagen types I, III, and, possibly, VI; reduce mucinous ground substance production; and increase collagenase activity. These mechanisms act by reducing the steady-state levels of mRNA. Studies examining the effects of intralesional injections of INF-alpha 2b and INF-gamma found them effective if injected immediately postoperatively into the excision site. INF-alpha 2b appears to normalize the increased collagen synthesis and glycosaminoglycan production by keloid fibroblasts, resulting in a reduction in the size of the keloid by approximately 50%.
This is performed immediately after surgery by injecting 1 million U to each linear centimeter of the skin surrounding the postoperative site. Another injection should be done 1-2 weeks later. INF-gamma injected weekly reduces the size and elevation of keloids, but the highest reduction obtained was 50% at 18 weeks.
5-fluorouracil (5-FU) injected intralesionally has been successfully used to treat small keloids. A mixture of 0.1 mL of triamcinolone acetonide (10 mg/mL) with 0.9 mL of 5-FU (50 mg/mL) produces the best results. It is injected into the keloid 3 times per week initially. Then, the frequency is adjusted according to response. Small keloids usually require 5-10 total injections given weekly. Painful injections are often the limiting factor.
Imiquimod induces local production of interferons at the site of application. It comes as a 5% cream and is started immediately after surgery and continued daily for 8 weeks. Patients with large surgical sites, flaps, grafts, or wounds closed with tension should not start imiquimod therapy for 4-6 weeks. The major side effect is mild-to-marked irritation at the site of application. Often, therapy must be stopped for several days then restarted. Hyperpigmentation develops in 50% of treated wounds.
Other medical therapies
Flurandrenolide tape (Cordran) used on a formed keloid will cause it to soften and flatten over time. This is placed on the keloid for 12-20 hours a day. It is also good at eliminating pruritus. Prolonged use will cause cutaneous atrophy.
Bleomycin (1 mg/mL) is used with success to treat small keloids.
Tacrolimus is a new treatment for keloids given twice a day. This is based on the data that it may mute the gil- 1 oncogene.
Methotrexate has proven quite successful in preventing recurrences when combined with excision. Dosing is 15-20 mg given in a single dose every 4 days, starting a week before surgery and continuing for 3 months.
Pentoxifylline (Trental) 400 mg 3 times a day has had some impact on decreasing recurrence. The mechanism is not fully known.
Colchicine inhibits collagen synthesis, microtubular disruption, and collagenase stimulation, and is thus used in the treatment of keloids.
Other medical therapies used with limited success include topical zinc, interlesional verapamil, cyclosporine, D-penicillamine, relaxin, and topical mitomycin C.
Because of the high recurrence rate of keloid scars, a follow-up period of at least 1 year is required to enable the start of treatment of recurrences as expediently as possible and to evaluate long-term success. Losing patients during follow-up care, only to have them return with full keloid recurrence, is not unusual.
Of the many therapies listed, nothing is reliably definitive. The failure of these treatments just highlights the essential problem in keloids, ie, that no clear molecular mechanism is defined for keloid development. Increased understanding at the molecular level will lead to development of new therapies. Several of the therapies listed are promising; however, studies thus far have been relatively small in scope, and further investigation is needed in regard to safety, adverse effects, and effectiveness of the therapy.
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