Keloids: Pathophysiology and Management
David T. Robles MD PhD; Erin Moore; Michelle Draznin MD; Daniel Berg MD Dermatol Online J. 2007;13(3) ?2007 Arthur C. Huntley, MD
Abstract and Introduction
Keloid formation occurs as a result of abnormal wound healing. Despite the high prevalence of keloids in the general population, they remain one of the more challenging dermatologic conditions to manage. More than a cosmetic nuisance, they are often symptomatic and can have a significant psychosocial burden for the patient. Although multiple treatment modalities exist, no single treatment has proven widely effective. In fact, recurrence following treatment is generally the norm. Combination therapy is likely the optimal strategy. In this review, we highlight the clinical features, pathophysiology and management of keloids.
A keloid may be defined as a benign growth of dense fibrous tissue developing from an abnormal healing response to a cutaneous injury, extending beyond the original borders of the wound or inflammatory response. Clinically, they are firm nodules, which can be skin colored, hypopigmented, or erythematous secondary to telangiectasias (Figs. 1-4). The color imparted by the telangiectasias is often of troubling cosmetic concern for the patient. Keloids are frequently symptomatic, with most patients reporting tenderness or pruritis. Lee et al., evaluated 28 patients with keloids and found that more than 80 percent of patients experienced keloid associated pruritus and about half experienced pain. Many patients are affected both physically and psychologically and report a severe negative impact on quality of life.
Keloids occur most commonly on the chest, shoulders, upper back, back of the neck and earlobes. For unknown reasons, keloids occur more frequently among Blacks, Hispanics and Asians and less commonly in Caucasians.[4,5] Female predominance has been noted but this may, in part, be reflected by the number of ear lobe keloids secondary to piercing among women. Unusual cases of massive keloids have been reported following severe burn injury and at the sites of vaccination. Genital keloids have been reported to occur subsequent to circumcision or following trauma.[9,10,11,12] In addition, multiple cases of corneal keloids following corneal trauma have been described. A history of keloids or hypertrophic scarring is considered a contraindication for performing multiple procedures, including LASIK eye surgery for myopia as well as CO2 laser resurfacing. Notwithstanding, a small case series of five Caucasian patients with keloids, reported good results after LASIK surgery with no complications or abnormal scarring.
On histologic examination, keloids are found to have increased collagen and glycosaminoglycan deposition, both major components of the extracellular matrix. The collagen in keloids consists of thickened whorls of hyalinized collagen bundles in a haphazard array, known as keloidal collagen. This is in contrast to normal scars where collagen bundles are oriented parallel to the skin surface.
The pathogenesis of keloids is complex and involves both genetic and environmental factors. It is widely accepted that keloids develop subsequent to injury or inflammation of the skin, but the exact pathogenesis is still unknown. Inflammatory skin conditions such as acne vulgaris, folliculitis, varicella infection, or vaccinations (particularly BCG vaccination) may induce keloid formation. Keloids most often occur in the setting of surgical or non-surgical wound healing (e.g., lacerations and earlobe piercing). Keloids often develop months after a wound or inflammatory process, but may develop as far out as a year later. Small needle sticks such as those during local anesthetic injection seemingly do not evoke keloid formation. However, the occurrence of a keloid or hypertrophic scar following BCG vaccination is not uncommon and is likely more to the inflammatory nature of the injection response rather than the size of the wound. In many cases, patients may not recall an inciting traumatic event or inflammatory process. These "spontaneous keloids" are postulated to have occurred in response to some form of inflammatory process perhaps forgotten or unrecognized by the patient.
Aberrant expression of various growth factors and their receptors has been described for keloid-derived fibroblasts. For example, keloidal fibroblasts have been shown to over express the growth factors: VEGF, TGF-β1, TGF-β2, CTGF, as well as the PDGF-α receptor.[17,18] Recent research has focused on elucidating the relationship between these over expressed growth factors and pathologic scarring. The question remains whether these growth factors cause keloid formation or simply increase in response to the scarring. TGF-β1 is a well-studied player in the pathogenesis of abnormal scarring and much research is focused on this pathway. A recent study by Capaner et al. reported that over expression of TGF-β1 is an important component in the formation of keloids, but is not a sufficient as an independent factor, giving credence to the hypothesis that keloid formation is a multifactorial process. Interestingly, despite widespread up regulation of growth factor receptors, keloidal fibroblasts have significantly reduced growth factor requirements in tissue culture. In one study, keloidal fibroblasts were found to have lower rates of apoptosis, thought to be related to a down-regulation of apoptosis-related genes.[20,21]
Compared to normal dermal fibroblasts, fibroblasts derived from keloids exhibit increased production of collagen and matrix metalloproteinases. Appropriate wound healing involves a delicate balance of increased collagen production and breakdown of tissue facilitated by matrix metalloproteinases. Analysis of the proliferation rate of keloid fibroblasts versus those derived from hypertrophic scars revealed an increased rate among keloid fibroblasts. Normal scars seem to have a negative feedback mechanism, whereby fibroblasts are mobilized to repair a cutaneous defect and their activity is appropriately dampened to prevent excessive repair. In this regard, fibroblasts derived from mature scars are capable of suppressing the in-vitro proliferation that may contribute to pathological scarring. This suggests the negative feedback mechanism is somehow defective in keloidal fibroblasts ultimately resulting in exuberant scar formation with the propensity to recur.
To date, no specific gene has been linked to the development of keloids. Most cases occur sporadically, although the finding of a positive family history is not unusual. Marneros and colleagues studied fourteen families with multiple affected members and derived an autosomal dominant with incomplete penetrance inheritance pattern based on their analysis. Various polymorphisms of genes encoding TGF-β1, β2, β3 as well as the TGFβ receptor have been evaluated, but no statistically significant associations with keloids have been identified.[27,28,29,30] It is likely that multiple genes impart susceptibility to keloid development, with different genes contributing to keloid formation in different families. This would make the identification of specific genes problematic. Recent advances in genetic technology allowing for the simultaneous analysis of multiple genes have significantly contributed to our knowledge of keloid pathogenesis. Satish et al. reported micro-array data comparing the gene expression profile from a small number of keloid tissue samples and normal skin. It is not surprising that they found increased expression of both fibronectin and the α-1 chain of type 1 collagen proteins that are commonly associated with abnormal wound healing. Additionally, several actin isoforms were over expressed in keloid fibroblasts. Interestingly, there were several apoptosis related genes that showed elevated expression in keloid fibroblasts, supporting the idea that disregulation of apoptosis may contribute to keloid formation. Of note, several tumor-related genes were found to be up regulated in keloid fibroblasts, with the greatest increase seen in Ribosomal Protein 18 (RPS18), an important protein for cell growth. Stat-3, another oncogene involved in cell proliferation, has also been linked to keloid pathogenesis. It is clear that analysis of multiple genes through microarray technology to compare gene expression among keloids and normal scars, holds promise for understanding the genetic control of keloids.
A wide range of therapies exist for keloids, with the most commonly used modalities being, intralesional steroid injection, surgical excision, cryotherapy, laser therapy, radiation therapy and the application of silicon gel sheets. Other treatments that have been used with variable success rates include, imiquimod, 5-FU, bleomycin, retinoids, calcium channel blockers, mitomycin C and interferon-α 2b. It should be noted that the bulk of the evidence for these modalities is based on smaller studies that employed little or no placebo control nor blinding of participants or researchers. A recent meta-analysis of 39 studies, representing 27 different treatments, reported a 70 percent chance of clinical improvement with any type of treatment. While this rate is encouraging, the effect was not statistically significant. Therefore, it is possible that current treatments may not have any significant effect on clinical improvement. Based on emerging information on keloid pathophysiology, there is a need for further studies in order to develop better therapies for pathologic scarring.
Intralesional Steroid Injection
Intralesional steroid injection is by far the most commonly used mode of therapy for keloids. Overall, this modality has a high degree of tolerability as well as effectiveness in reducing symptoms. Several studies evaluating intralesional steroids have reported roughly a 50 percent recurrence rate.[35,36,37,38,39] Triamcinolone acetonide (Kenalog; Bristol-Myers Squibb, Princeton, NJ) is typically used at a concentration ranging from 10 to 40mg/ml, depending on the size and location of the lesion. For lesions on the trunk or extremities therapy is usually initiated at 40mg/ml and then titrated accordingly at subsequent visits. Multiple injections at regular monthly intervals are generally required for larger keloids. Intralesional steroid injections help soften and reduce symptoms of pruritus and tenderness. The complications of intralesional steroid use include, skin atrophy, hypo- or hyperpigmentation, and the development of telangiectasias. Because patients typically require multiple needle sticks, especially for larger lesions, some authors advocate pre-treatment with topical lidocaine or the addition of lidocaine in the syringe to help alleviate injection-associated pain. Triamcinolone acetonide has been shown to inhibit collagen synthesis and fibroblast growth in vitro. It has been reported that treatment of fibroblasts with triamcinolone acetonide results in a reduction in TGF-β expression and an increase in bFGF production. Intralesional steroid injection may be impractical for very large or multiple keloids, since the pain of injection may be considerable and there is additional concern due to large doses of corticosteroids.
Surgical excision of keloids should be performed with considerable caution because the rate of recurrence is high. Surgical excision may be gratifying, providing an immediate cosmetic correction. However, the excision often leads to a longer scar and the potential for a larger keloid in the event of recurrence. Adjuvant therapies such as post-excisional steroid injections should be considered. Some preliminary reports suggest topical Imiquimod as an adjunct following excision, but long term follow-up data are lacking. There are also data suggesting the benefit of topical Mitomycin C as an adjunct to surgical excision, however these are also small studies with short-term followup. A small case series of four patients reported superior results when collagen-glycosaminoglycan copolymer neodermis (Integra) was placed at the time of excision and skin grafting was delayed for several weeks. The best surgical outcomes are seen with excellent wound edge closure, combining minimal tension with maximal eversion and ensuring incisions are made along relaxed skin tension lines. Patients with a history of keloid or hypertrophic scar formation should avoid elective surgery or cosmetic procedures to avoid risk of future keloids.
Cryotherapy has been used for smaller lesions, but its use is limited by considerable pain and sometimes prolonged healing following treatment. Because multiple treatments are often required, the risk for hypopigmentation in darker-skinned patients is a significant drawback. Cryotherapy has been reported to alter collagen synthesis and induce keloidal fibroblast differentiation towards a more normal phenotype. Some authors advocate the use of cryotherapy just prior to steroid injection in order to induce edema and thus facilitate streroid injection.
Multiple studies utilizing radiation therapy as an adjunct to surgical excision have been reported, but the lack of a standardized regimen makes comparisons between studies difficult.[49,50,51,52] Various techniques can be found in the literature, including superficial x-rays, electron beam, and low- or high-dose rate brachytherapy. Post-excisional radiotherapy is typically employed immediately following surgical excision. When combined with excision, efficacy rates are higher, ranging from 65 to 99 percent. In one retrospective study, single-fraction radiotherapy within 24 hours of surgical excision was associated with an 80 percent recurrence-free success rate at 5-years followup. In a separate retrospective study assessing the efficacy of 15-Gy-electron beam irradiation with more than 18-months followup, a 77 percent recurrence free success rate was reported.
Side effects of radiation therapy include transient erythema and hyperpigmentation. The risk of carcinogenesis from radiation therapy of keloids is likely to be extremely low, especially with modern techniques. Rare cases in the literature discussing a potential association of malignancy with radiotherapy of keloids can be found[54,55] but determining causation is difficult. Given the uncertainty of the risk, it is recommended by some authors to limit radiotherapy to those who have failed previous excisional treatments and to patients 21 years of age or older.
The use of lasers for keloid ablation has been disappointing. The use of the carbon dioxide and argon lasers has been associated with recurrence rates as high as 90 percent. The most promising results have come from the use of the 585nm pulsed dye laser (PDL).[56,57] Use of the pulsed dye laser in combination with intralesional steroid injection may also help soften the lesions and enhance the integration of steroid. Work by Kuo and colleagues showed that flashlamp pulsed-dye laser treatment is associated with a down-regulation of TGF-β1 and up-regulation of the metalloproteinase MMP-13, suppression of keloidal fibroblast proliferation as well as induction of apoptosis.[59,60] Use of the Nd:YAG laser as a monotherapy or in conjunction with intralesional triamcinolone injection has shown some promising results with a large percentage of patients remaining keloid-free at follow-up.
Silicone Gel Sheeting
Silicone gel dressings are a non-invasive and relatively inexpensive adjunctive treatment modality for keloids. Recently, an international expert panel recommended silicone gel sheet therapy as a first line prophylaxis following surgical excision. When used after surgical excision, 70-80 percent of keloids and hypertrophic scars did not recur during followup. The gel sheets provide an occlusive barrier and seem to soften scars by increasing hydration and have a significant effect on reducing erythema, pain and itching. Following surgical excision the silicone gel sheets are applied as soon as re-epithelialization is achieved and are worn for at least 12 hours per day. The sheets last approximately 10-12 days and may be washed and reapplied. A study comparing the effect of silicone versus non-silicone gel sheets found that non-silicone gel sheets were equally effective in reducing scar size, induration and symptoms, suggesting that occlusion is all that is needed for the effect. However, a recent Cochrane review evaluating the effect of silicone gel sheeting on prevention and treatment of keloids concluded that effects are unclear because of the preponderance of poor quality research. They report that high quality research would benefit both patients and practitioners in their efforts to combat pathological scarring.
Imiquimod is a topical immunomodulator which is FDA approved for the treatment of external genital and perianal warts and most recently, for the treatment of actinic keratoses. It functions through the toll-like receptor 7 and is known to upregulate pro-inflammatory cytokines, including TNF-α is known to reduce collagen production in fibroblasts and thus, topical Imiquimod has been studied as an adjunct to surgical therapy.[66,67] Following surgical excision, topical imiquimod 5 percent cream was applied each night to the suture line and surrounding area for a total of 8 weeks. Itching, burning, pain and blisters were the reported side effects. Although no recurrences were noted, followup was limited to 24 weeks. In another small and uncontrolled study, imiquimod therapy following excision of eight earlobe keloids resulted in a 25 percent recurrence. A similar study, also looking at the effect of adjunct imiquimod after surgical excision of earlobe keloids, reported no recurrence in 8/8 keloids treated with the combination therapy. The caveat in interpreting these studies is that the follow-up was limited to approximately 6 months and many keloids recur long after this time point. Keloids may recur with a median of more than 12 months following treatment, thus follow up at 6 months could potentially overestimate the efficacy of treatment. Followup for any keloid intervention should extend to at least 1 year, and perhaps even as long as 2-3 years. Given the small numbers treated and the lack of long-term follow up, the overall clinical benefit of imiquimod is still unclear.
5-Fluorouracil (5-FU) is a pyrimidine analog that is converted intracellularly to a substrate that causes inhibition of DNA synthesis by competing with uracil incorporation. The increased rate of proliferation seen in keloidal fibroblasts suggest that 5-FU may be effective in limiting keloid growth. However, several studies in the literature suggest that the overall efficacy is not better than other modalities and significant side effects such as ulceration and hyperpigmentation make topical 5-FU less appealing.[74,75,76] A major drawback of systemic 5-FU is its association with anemia, leukopenia and thrombocytopenia. Thus, even intralesional 5-FU should be avoided in pregnant and lactating females and patients with concurrent infections or bone marrow suppression.
Bleomycin, a chemotherapeutic agent used in many cancers, also has several dermatologic uses. Bleomycin has widespread effects at the cellular level, including blocking the cell cycle, degrading DNA and RNA, and producing reactive oxygen species. A clinical trial of 13 patients with keloids or hypertrophic scarring showed significant improvement after treatment with intralesional bleomycin. Another recent study of 45 patients, compared bleomycin to a combination of cryotherapy and intralesional triamcinolone. In this study, a technique termed bleomycin tattooing was used. Multiple punctures were made in the lesions and bleomycin was applied topically to the areas. Overall, patients in the bleomycin group showed significantly greater degree of flattening than patients treated with cryotherapy and intralesional triamcinolone, though the therapeutic effect was greatest in keloids with a volume greater than 100 mm2. Transient hyperpigmentation was seen in 75 percent of patients in the bleomycin treatment group, although this faded in the majority of patients by three months post treatment. Hypopigmentation and telangiectasia were the most common complications of combination cryotherapy and triamcinolone. In the three months of follow-up reported, there were no recurrences. However, as previously stated, this followup is short given that keloids may recur years after treatment. These small studies indicate bleomycin may have therapeutic potential in treating keloids, however there is a need for larger trials that employ more rigorous methodology.
Interferons are cytokines that modulate the activity of growth factors and have been shown to have both antiproliferative and antifibrotic effects. There are data to indicate interferons may increase collagenase activity and could provide therapeutic potential for keloids through this mechanism. However, studies looking at interferon α-2b as a single agent have been disappointing. Davison et al. recently published results from the first trial looking at interferon α-2b as an adjunct to surgical excision. The trial enrolled 50 patients and randomized half to receive intralesional interferon alpha-2b and half to receive intralesional triamcinolone. The injections were given immediately after excision and also one week later at a dosage of million units per centimeter of scar with a maximum of five million units. Patient follow up occurred at 1 week, 1 month, 6 months and 1 year post surgery. Unfortunately, half of the patients randomized to the treatment arm dropped out of the study prior to receiving injections. This was attributed to concern over side effects and the cost of interferon treatment (around $100 per treatment), which is usually not covered by insurance and was not funded by the study. The study was halted early because of a significantly greater rate of recurrence in the treatment group (54% versus 16%) with the group concluding that intralesional interferon α-2b is not an effective treatment as an adjunct to excisional surgery.
Patients with a previous keloid or a family history of keloids are at increased risk for developing abnormal scars. These patients should be counseled against body piercing and should avoid elective cosmetic procedures with a risk for scarring. As discussed above, wounds should be closed with minimal tension and the use of adjunctive measures following surgical excision including the use of silicone gel sheets may reduce recurrence.
Despite their common occurrence and the multitude of treatment modalities available, keloids remain a significant challenge for both the clinician and the patient. The lesions are often symptomatic and troubling cosmetically, resulting in a significant negative psychosocial burden for the patient. Intense research is underway to better understand the pathophysiology of the abnormal processes leading to keloid formation. This will likely lead to more specific and effect treatments in the future. For now, our greatest weapon lies in patient education, combination therapy, and prevention.
Daniel Berg MD firstname.lastname@example.org
David T. Robles MD PhD, Erin Moore, Michelle Draznin MD, and Daniel Berg MD, Department of Medicine, Division of Dermatology, University of Washington Medical Center, Seattle