You are in: eMedicine Specialties > Plastic Surgery > WOUND HEALING Wound Healing, KeloidsArticle Last Updated: Sep 27, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: R Edward Newsome, MD, Associate Professor, Program Director and Chief, Department of Surgery, Section of Plastic Surgery, Tulane University Health Sciences Center R Edward Newsome is a member of the following medical societies: American College of Surgeons, American Medical Association, American Society of Plastic Surgeons, and Louisiana State Medical Society Coauthor(s): Robert P Bolling, MD, MPH, Fellow, Department of Plastic and Reconstructive Surgery, Tulane University School of Medicine; Katherine Langston, MD, MSPH, Staff Physician, Department of Surgery, Tulane University Medical Center; Alun Wang, MD, Assistant Professor, Department of Pathology, Tulane University Medical Center; David A Jansen, MD, FACS, Private Practice, Surgical Associates LLC Editors: Christian Paletta, MD, FACS, Professor, Division Chief and Program Director, Department of Plastic and Reconstructive Surgery, St Louis University School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Wayne Stadelmann, MD, Stadelmann Plastic Surgery, PC; Nicolas (Nick) G Slenkovich, MD, Practice Director, Colorado Plastic Surgery Center at Swedish Medical Center; Jorge I de la Torre, MD, FACS, Professor of Surgery and Physical Medicine and Rehabilitation, Residency Program Director, Division of Plastic Surgery, University of Alabama at Birmingham; Director, Center for Advanced Surgical Aesthetics Author and Editor Disclosure Synonyms and related keywords: wound healing, keloids, keloid scar, abnormal scar formation, dermal fibrotic lesion, abnormal scarring, surgical scarring, abnormal scar, surgical scar, excessive wound healing, crab-claw scar, crab claw scar, fibroproliferative disorder, wound complication, scar complication DEFINITION AND HISTORICAL BACKGROUNDSection 2 of 11
  The first description of abnormal scar formation in the form of keloids was in the Smith papyrus in approximately 1700 BC. Ancient African folklore depicted descriptions of keloids, and ancient African art included representations of keloid scars. 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. EPIDEMIOLOGYSection 3 of 11
The excessive wound healing in both hypertrophic scars and keloids is found only in humans and occurs in 5-15% of wounds. Both types of scars tend to be familial, but this is much more true for keloids. Apparently, men and women are affected equally, although a higher incidence exists of women presenting with keloids, possibly secondary to the cosmetic implications associated with the disfigurement. The average age at onset is 10-30 years. Persons older than 65 years rarely develop keloids. RACESection 4 of 11
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. GENETICSSection 5 of 11
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. No consistent pattern exists in the mode of genetic transmission, which is reported to occur as both an autosomal dominant and autosomal recessive pattern. More recent evidence has shown an increase in expression of the gil-1 oncogene. PATHOPHYSIOLOGYSection 6 of 11
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. 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. PHYSICAL EXAMINATIONSection 7 of 11
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. HISTOLOGYSection 8 of 11
The 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. Disagreement exists about whether hypertrophic scars can be differentiated from keloids using light microscopy. Blackburn and Cosman described eosinophilic refractile hyaline collagen fibers, an increase in mucinous ground substance, and a lack of fibroblasts in keloids. Scanning electron microscopy findings clearly demonstrate the randomly organized sheets of collagen with no obvious relationship to the skin surface in keloid scar formation. THERAPYSection 9 of 11
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. Occlusive dressings 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. Compression 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. Corticosteroids Pharmacological therapy has long been a mainstay 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. Excisional surgery 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. Recurrence rates with surgery alone range from 45-100%. Excisional therapy is most effective when combined with external radiation, steroid injection, pressure therapy, or a combination thereof. Radiation 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 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. Some newer 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. Children should not be irradiated unless this is the only viable option. If so, the metaphyses should be shielded. One case of medullary carcinoma of the thyroid has been reported in an 8-year-old boy after excision and postoperative radiation. Cryosurgery 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 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. Laser therapy 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. The carbon dioxide laser (wavelength, 10,600 nm), when used as a sole modality, has recurrence rates of 39-92%; when combined with intralesional steroids, the rate of recurrence is 25-74%. The Nd:YAG laser (wavelength, 1064 nm) has demonstrated recurrence rates of 53-100%. Interferon therapy The newest therapeutic modality on the horizon 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-Fluoruracil 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 therapy 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. MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
Wound Healing, Keloids excerpt Article Last Updated: Sep 27, 2006 | |||||||||||||||||||||||||||||||||||||||||||||||
