A Primary Care Perspective on Keloids

Abstract

Keloids are a common presenting complaint in the primary care clinic. This condition presents a formidable challenge, as recurrence is often difficult to prevent despite use of multiple therapeutic interventions. Part of the reason for the absence of a definitive treatment is the incomplete understanding of the pathogenesis of keloid formation, which creates a frustrating situation for both physician and patient. Here we review the most recent literature on the clinical features, pathogenesis, and management of keloids, with special emphasis on the unique challenges faced by primary care physicians.

Introduction

Keloids have been recognized since antiquity. The term keloid was chosen based on the Greek word for crab claw (“cheloid”)[1] Keloids result from wound healing gone awry. Formation is commonly seen after invasive medical procedures; elective cosmesis (tattoos and piercings); and mundane events, such as insect bites and trauma from scratching. Symptoms can extend beyond cosmesis. One survey reported pruritus in 27% of patients and pain in 19%.[2] Rarely, keloids have also been shown to ulcerate and develop draining sinus tracts. The most common anatomical sites for keloids include the chest, shoulders, earlobes, upper arms, and cheeks.[3] Although keloid formation has been traditionally understood to result from indefinite collagen production, no single accepted hypothesis has been accepted to fully explain the pathological mechanism.[4]

Epidemiology

Keloids are more common in dark-skinned persons. Incidence is estimated to be between 4.5% to 16% among blacks and Hispanics.[5] Keloids occur with equal frequency in men and women. Younger patients are affected more often, with an age range of 10 to 30 years.[6] A genetic predisposition to keloids has been described, and it is inherited in an autosomal dominant fashion.[7]

Diagnosis and Differential Diagnosis

When an overgrowth of scar tissue is being evaluated, the most immediate differential diagnosis to consider is the hypertrophic scar. Differentiating between the 2 diagnoses is essential because keloids and hypertrophic scars are separate clinical and histochemical entities. Phenotypically, hypertrophic scars remain within the confines of the original scar border, whereas keloids invade adjacent normal dermis.[8] The morphology of the hypertrophic scar is shown in Figure 1.

Figure 1.

Two angles of a 40-year-old black woman with a hypertrophic scar following right-sided open cholecystectomy.

Although the scar is inappropriately large, it remains confined to the wound site. In contrast, the keloid grows well beyond the margins of injury (Figure 2).

Figure 2.

Close-up of keloid with typical raised area with flat surface. The base is wider than the top.

In addition to morphologic differences, the timeline between the 2 entities differs greatly. Hypertrophic scars generally arise within 4 weeks of the initial scar, grow intensely for several months, and then regress. Figure 3 shows gradual regression of a hypertrophic scar on a patient's lower back.

Figure 3.

Young white female with hypertrophic scar at initial presentation (top panels) and after gradual regression (lower panels).

In contrast, a considerable amount of time may elapse before a keloid and an initial scar appear. Beyond this, the keloid may proliferate indefinitely.[6,9]

On histology, both keloids and hypertrophic scars exhibit increased fibroblast density. However, only keloid formation is associated with increased fibroblast proliferation.[9] The collagen fibers in keloids are larger, thicker, and wavier and have a random orientation, whereas those in hypertrophic scars are oriented parallel to the epidermal surface.[10]

Biochemical markers can also distinguish keloids from hypertrophic scars. Concentrations of alanine transaminase and adenosine triphosphate are higher in keloids than in normal scar tissue and hypertrophic scars.[11] Furthermore, fibroblasts isolated from keloids and hypertrophic scars have different mRNA transcription sequences – keloids have an increased ratio of type I to type III collagen.[12]

Dermatofibrosarcoma protuberans (DFSP), a slow-growing, locally invasive fibrohistiocytic tumor, must also be distinguished from a keloid. It may initially present as a hard, discrete plaque that can range from violaceous to pink and is usually asymptomatic. Like a keloid, DFSP often presents on the trunk and is associated with a history of trauma in up to 20% of cases. Histopathologic examination is often the best way to differentiate between these lesions. DFSP exhibits characteristics of a well-differentiated fibrosarcoma. It consists of densely packed, monomorphous, spindle-shaped cells with elongated nuclei that are organized as fascicles in a storiform arrangement.[13] On the other hand, keloids consist of thickened whorls of hyalinized collagen that lack any particular orientation.

Other diagnoses to consider when examining a keloid-like lesion include dermatofibroma, desmoid tumor, scar with sarcoidosis, and foreign body granuloma.[14]

Pathogenesis

As mentioned earlier, the cause of keloid formation is still not understood, and several theories have been proposed. A few are reviewed below.

Alteration in Milieu

Keloids result from excess scar tissue secondary to increased growth factor activity and alterations in the extracellular matrix. Keloid fibroblasts are known to have a heightened sensitivity to tumor growth factor (TGF)-beta, which is normally produced during the proliferative phase of wound healing.[15,16] Similarly, keloid fibroblasts have a 4- to 5-fold increased level of platelet-derived growth factor receptor, which results in a synergistic growth-stimulator effect with TGF⁻beta.[17]

Also, the extracellular matrix that regulates growth factors is abnormal. Keloids often have elevated levels of fibronectin and certain proteoglycans as well as decreased levels of hyaluronic acid.[18] Fibronectin and hyaluronic acid are proteins expressed during normal wound healing, and their dysregulation contributes to the fibrotic phenotype seen in keloids.[19,20]

Collagen Turnover

Abnormal regulation of the collagen equilibrium leads to the characteristic appearance of a keloid because the collagen content is higher than in normal tissue or scar tissue.[2,8] Although the collagen is disorganized with thicker and wavier bundles, the hallmark of the keloid structure is the “collagen nodules” present at the microstructural level.[21] Also, the ratio of type I to type III collagen is significantly increased in keloids due to alterations at the pretranscriptional and posttranscriptional levels.[12]

Collagen is mainly produced by fibroblasts and to some extent endothelial cells.[7,21,22] Keloid fibroblasts have a greater capacity to proliferate because of a lower threshold to enter the S phase of mitosis, resulting in greater autonomous production of collagen.[3,18,22,23] The collagen produced by fibroblasts is normally degraded by the enzyme collagenase synthesized by fibroblasts and inflammatory cells.[21,22] Enzymes that inhibit or degrade collagenase exert an additional level of collagen regulation.[22,24] Concentrations of collagenase inhibitors, namely alpha-globulins and plasminogen activator inhibitor-1, are consistently elevated in both in vitro and in vivo keloid samples, whereas levels of degradative enzymes are frequently decreased.[22,24]

Genetic Immune Dysfunction

An inherited abnormal immune response to dermal injury may cause keloid formation, as these lesions are associated with particular human leukocyte antigen subtypes. Studies suggest an association between group A blood type and human leukocyte antigen B14, 21, BW35, DR5, and DQW3 in patients with a keloid diathesis.[25] Patients who develop keloids have a disproportionately high incidence of allergic diatheses and elevated levels of serum immunoglobulin E.[26] Multiple reports have found patterns in the serum complement, immunoglobulin G, and immunoglobulin M levels in patients with keloids, suggesting a systemic immune state genetically predisposed to keloid formation.[27,28] In this way, keloid formation could be considered an autoimmune connective tissue disease.

Sebum Reaction

According to the sebum reaction theory, keloids arise from an immune reaction to sebum. Dermal injury exposes the pilosebaceous unit to the systemic circulation, initiating a cell-mediated immune response in persons who retain T lymphocytes sensitive to sebum. Subsequent release of cytokines, including various interleukins and TGF-beta, stimulates chemotaxis of mast cells and production of collagen by fibroblasts. As the keloid expands, further pilosebaceous units on the advancing border are disrupted, leading to further propagation.[29,30] Keloids preferentially occur in areas with a high concentration of sebaceous glands, including the chest wall, shoulder, and pubic area, while rarely occurring in areas relatively devoid of sebaceous glands, such as the palms and soles. Because humans are the only mammals with true sebaceous glands, the sebum reaction hypothesis partly explains why keloids only occur in humans.

Management

Although multiple management options are available for the treatment of keloids, they can be expensive and recurrence rates remain high. Therefore, prevention is paramount. Patients with a family history of keloids should avoid ear piercing, and those with a personal history should avoid elective surgical procedures, including LASIK surgery and CO₂ laser resurfacing.[31] Keloid development from dermatologic conditions, such as acne vulgaris, folliculitis, and varicella infection, should be a strong concern in high-risk individuals and should therefore be treated aggressively. Although small needlesticks are not associated with great risk for keloid formation, they have been known to occur following bacille Calmette-Gu&$233;rin vaccination.[32]

Intralesional steroids are the most effective and widely used treatment for keloids. Intralesional triamcinolone acetonide, a potent anti-inflammatory fluoridated hydrocortisone, is often used as first-line therapy for keloids. The preferred method of delivery is intralesional injection. One study reported that intralesional injection of triamcinolone acetonide led to symptomatic improvement in 72% of patients and complete flattening in 64% of lesions.[33] However, the long-term cure rates remain equivocal. One study found a 5-year recurrence rate of 50% when triamcinolone acetone was used as monotherapy.[34]

The typical dose regimen of triamcinolone acetonide is 10 mg per linear centimeter of keloid every 2 to 6 weeks until clinical resolution. Triamcinolone acts by a variety of mechanisms to reduce collagen synthesis. Steroids have been shown to bind to glucocorticoid receptors on fibroblasts and downregulate both normal and keloid-derived fibroblasts and inhibit extracellular matrix production.[35]

Adverse effects occur in approximately half of patients treated with triamcinolone and include subcutaneous atrophy, telangiectasia, and pigmentary changes. It should be noted that these side effects frequently resolve without intervention.[36] Adverse systemic effects of steroids generally do not occur with intralesional triamcinolone treatment, but rare cases have been reported.[37]

Figure 4 shows an earlobe keloid before and after successful treatment with intralesional steroids.

Figure 4.

19-year-old Hispanic woman with an earlobe keloid before (top panels) and after (lower panels) treatment with steroid injection.

Surgical excision of keloids generally results in recurrence of lesions, with rates ranging from 40% to 100%.[38] Simple excision is believed to stimulate additional collagen synthesis, resulting in rapid regrowth and often a larger keloid.[39]

Radiation therapy has been shown to effectively reduce the recurrence rate of keloids. It works by directly damaging fibroblasts, which alters collagen structure and organization.[40] In vitro studies have shown radiation therapy to increase the rate of apoptosis in keloid fibroblasts, returning the cell population to equilibrium.[41] Ogawa and colleagues studied the efficacy of postexcision radiation therapy while attempting to determine the optimal radiation dose. A total of 109 patients with 121 keloid and intractable hypertrophic scar sites were given electron-beam irradiation at total doses of 10, 15, or 20 Gy, depending on the site. This group was compared with 218 patients with 249 keloid and intractable hypertrophic scar sites treated with the old protocol of surgical removal followed by irradiation at 15 Gy (without variation by site). Median follow-up for the 2 groups were 26 and 23 months, respectively. Recurrence rates in the group receiving the site-dependent radiation protocol were substantially reduced, from 29.3% to 14%.[42]

Acute side effects include erythema, inflammation, edema, desquamation, and ulceration. Chronic changes include changes in pigmentation, skin atrophy, and fibrosis. Despite the presence of a few documented cases, there has been no clear association between radiation therapy and carcinogenesis as witnessed in multiple large-scale clinical trials.[43]

Silicone gel has been approved by the U.S. Food and Drug Administration as an effective adjunct to keloid excision and as prophylaxis to prevent abnormal scarring following elective incisions.[44,45] Silicone gel can be administered either as a topical gel or impregnated elastic sheet. However, one of the primary limiting factors is poor patient compliance. The patient needs to be instructed to cover the entire scar for at least 12 hours each day and ideally up to 24 hours per day, except when the skin is being cleaned. If used correctly, silicone gel has been shown to induce more rapid healing and can be used in conjunction with CO₂-laser excision to decrease recurrence rates.[46,47]

Although its precise mechanism of action is unknown, silicone gel is thought to act as an impermeable membrane that keeps the skin hydrated, functioning in a manner analogous to the stratum corneum. Adverse effects of silicone gel include occasional skin maceration, erosion, rash, and pruritus, all of which resolve within several days after gel removal.[48,49]

In addition to silicone gel, pressure therapy following excision is effective and causes minimal adverse effects. The mechanism of pressure therapy has yet to be determined but may be through pressure-induced ischemia that promotes collagen degradation and modulates fibroblast activity.[50,51] Because compression earrings should be worn 24 hours per day after suture removal, patient compliance can be an issue. Nevertheless, regardless of whether it is used on the earlobe or other parts of the body, pressure therapy is simple and highly efficacious with minimal adverse effects.

Laser therapy has been advocated but has not been shown to be effective in managing keloids. Some investigators have combined the CO₂ laser with various modalities, including interferon, triamcinolone, and silicone gel. This has resulted in success rates similar to treatment with scalpel excision with adjuvant therapy.[47,52] However, the cost of the laser and the recurrence rate prohibit its use over the scalpel.

Numerous studies have espoused the use of laser therapy in treating keloids. The use of the 585-nm flashlamp-pumped pulsed-dye laser on selected patients has demonstrated efficacy exceeding 75% while incurring minimal morbidity.[53,54] The main problem with laser treatment is that melanin is a competing chromophore; thus, the laser loses efficacy when used on darker-skinned persons. This essentially makes it less useful on the population at greatest risk for keloid formation.

Intralesional 5-fluorouracil is an experimental therapy for keloids that has shown some potential in preliminary trials. 5-fluorouracil is an antimetabolite that inhibits fibroblast proliferation and modestly reduces keloidal scarring.[55,56] A retrospective study on more than 1000 patients examining the effect of intralesional administration of 5-fluorouracil as single therapy for keloids showed a promising initial response. However, the lesion invariably recurred. A high recurrence rate therefore necessitates serial administrations.[55] Adverse effects have been rare and limited to superficial skin irritation.[55,56]

Additional strategies for keloid management reported in the literature include intralesional injection of calcium-channel blockers, cryosurgery, and antihistamines.[57–59] Several experimental therapies for abnormal scarring include bleomycin, imiquimod, and cyclosporine. Their use has been restricted to single case reports or small trials and will probably be investigated further.[60–62]

Conclusion

No ideal therapy exists for treating keloids, which reflects the current partial understanding about the pathogenesis of the disease. Optimal treatment continues to be various combinations that focus on decreasing recurrence rates. The most effective combination has yet to be found. However, developing a thorough understanding of the current state of management options allows physicians to improve baseline care for patients having to deal with the often- frustrating course of recurrent keloids.