Keloids and hypertrophic scars

INTRODUCTION — Hypertrophic scars and keloids are fibroproliferative disorders that result from aberrant wound healing in predisposed individuals following trauma, inflammation, surgery, or burns. While hypertrophic scars do not exceed the margins of the original wound, keloids are characterized by continuous growth and invasion into the adjacent, healthy skin beyond the original wound boundary [1]. Keloids are often associated with pain and itch, can be disfiguring, and impair function and quality of life. Keloids also have a marked tendency to recur when surgically excised. Although hypertrophic scars and, especially, keloids are widely perceived as difficult to treat and at high risk of recurrence, advances in the understanding of the pathophysiology of abnormal scars has led to improved therapeutic approaches and outcomes [2,3].

This topic will discuss the pathogenesis, clinical manifestations, management, and prevention of hypertrophic scars and keloids. Hypertrophic scars and keloids following burn injuries are discussed separately. Laser treatment of keloids is also discussed separately. (See "Hypertrophic scarring and keloids following burn injuries" and "Laser therapy for hypertrophic scars and keloids".)

EPIDEMIOLOGY — Keloids are reported in all ethnic groups. They can occur sporadically or show a familial pattern. Based on limited epidemiologic data, the risk of keloid development appears to be highest in individuals with African or Asian ancestry. An analysis of data from the United States National Ambulatory Medical Care Survey from 1990 to 2009 that included 8,550,000 visits for keloids showed that when examining the number of visits per 100,000 United States residents according to ethnicity, African Americans and Asian Americans made the highest number of visits for keloids, nearly 3 and 2.5 times as high as non-Hispanic White Americans, respectively [4].

There are no high-quality data on the prevalence and incidence of keloids. In two African studies, keloid prevalence among patients attending dermatologic clinics was 3.5 percent [5,6]. In a Kenyan study, the prevalence of keloids among people with any scar on their body was 8.3 percent [7]. An analysis of the Taiwanese National Health Insurance Research Database estimated an annual incidence rate of keloids of 0.15 percent [8].

CLASSIFICATION — Scars have been traditionally classified based on their clinical features (table 1). To help unify the clinical definition of keloids and hypertrophic scars, the Japan Scar Workshop (JSW) created a tool for objectively diagnosing keloids and hypertrophic scars. This tool, called the JSW 2015 Scar Scale (JSS 2015), involves scoring the risk factors of individual patients and the lesion characteristics. Studies are needed to assess whether the JSS 2015 can accurately diagnose keloids in other populations.

ETIOLOGY AND PATHOGENESIS — The unrestrained growth of keloids and hypertrophic scars has led some authors to designate these lesions as tumors. However, while tumors are cell proliferative disorders, keloids and hypertrophic scars are fibroproliferative disorders driven by chronic inflammation. The absence of tumor-like cells or structural atypia on histopathology suggests that they are hyperplastic disorders incited by external or internal stimuli.

In predisposed individuals, the main inciting factor for hypertrophic scars and keloids is injury to the reticular layer of the dermis, including by surgery, burns, and trauma. In individuals with a high propensity to develop keloids, these can arise from extremely minor injuries, such as infection in the deep part of the hair follicle (folliculitis) or even insect bites.

Dysregulation of the wound healing process — The pathogenesis of keloids and hypertrophic scars, although incompletely understood, involves a dysregulation in one or more of the wound healing phases (ie, inflammatory, proliferative, and remodeling). Multiple cell types participate in pathologic scarring, including fibroblasts, myofibroblasts, keratinized cells, melanocytes, mast cells, and vascular endothelial cells. While all contribute to the development of abnormal scars, the vascular endothelium may play a particularly prominent role. Some lines of evidence suggest that pathologic scars are due to endothelial dysfunction that leads to vascular hyperpermeability during the inflammatory phase of wound healing [9]. This results in continued influx into the dermis of inflammatory cells and factors, resulting in unrelenting, local inflammation and fibrotic activity [9-12].

At the molecular level, many inflammatory cytokines and growth factors have been found in pathologic scars. Of particular importance may be transforming growth factor (TGF)-beta, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), interleukin (IL) 6, and IL-8 [13,14]. The activation of several signaling pathways, including TGF-beta/Smad, mitogen-activated protein kinase (MAPK), Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK), Wingless-related integration site (Wnt)/beta-catenin, and tumor necrosis factor (TNF)-alpha/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), are likely to play a role in fibroblast activation and increased production of extracellular matrix [15]. However, despite considerable research implicating vascular dysfunction, inflammation, and fibrosis in keloid/hypertrophic scar pathogenesis, the exact mechanisms remain to be fully elucidated.

Local tissue factors

Mechanical stretching forces — The external mechanical forces that are placed on the wound/scar during daily life are a primary factor involved in abnormal scar formation. Multiple lines of evidence suggest that stretching forces can both cause and worsen pathologic scars, particularly when genetic and systemic factors are also in play. Supporting the importance of local mechanical forces in keloid development is the observation that keloids have a strong predilection for body locations that are prone to frequent skin stretching and contraction (eg, the anterior chest and scapula). By contrast, they rarely occur where skin tension is uncommon (eg, the parietal region of the scalp, anterior lower leg, and upper eyelid) [16]. These regional differences can be seen even in patients with multiple/large keloids.

Moreover, keloids often develop in distinctive, site-specific shapes that reflect the direction(s) of the prevailing local stretching forces. Examples are the butterfly, crab's claw, and dumbbell on the shoulder, anterior chest, and upper arm, respectively [16-18]. This observation suggests that skin tension augments the cutaneous inflammation in the region of the scar that receives most of the force into the normal surrounding skin, thereby generating a leading edge and spreading of the scar.

Stretch-driven pathologic scar growth is mediated by mechanoreceptors on the immune cells, endothelial cells, and fibroblasts in the scar. When the skin is stretched, a force is applied to cells and the extracellular matrix surrounding these cells, triggering their mechanoreceptors [19]. This results in increased production of inflammatory cytokines and persisting inflammation, increased vascular permeability, and increased production of extracellular matrix [10].

Stretching forces also promote a continued production of stiff immature collagen that does not undergo remodeling as in normal wound healing. It should be noted that in the absence of additional risk factors for pathologic scars, when the stretching force applied to the scar is not excessive, the stretch-inflammation-growth cycle will eventually wane, and the scar will mature. This is what often happens to classic hypertrophic scars. However, if a hypertrophic scar is on a joint, whose movements place huge stretching forces to the scar, it will continue growing and ultimately lead to contractures. If other keloid-predisposing factors are also present, keloids will form instead of hypertrophic scars.

The discovery of the key role of local mechanical force in pathologic scarring and its connection to inflammation has informed the approach to the management of keloids and hypertrophic scars. Strategies that minimize local tension (eg, certain conservative and surgical approaches) and/or reduce inflammation (eg, topical or intralesional corticosteroids, antiangiogenic treatments) are routinely used to treat and prevent pathologic scarring [20]. (See 'Prevention' below and 'Treatment of hypertrophic scars' below.)

Other local factors — Cutaneous infections associated with dermal inflammation can lead to pathologic scarring in predisposed individuals. Examples include folliculitis in hairy regions of the body; acne on the face, neck, chest, and back; infected earlobe piercing; and burn wounds. Intradermal administration of vaccines can also rarely cause pathologic scarring due to dermal injury and subsequent inflammation [21].

Patient-related factors

Genetics — Several observations suggest that there is a genetic predisposition to keloid formation. Keloids often occur in families. Studies of multiple pedigrees with familial keloids suggest an autosomal dominant pattern of inheritance with incomplete penetrance and variable phenotypic expression [22-24]. Although genetic studies have identified susceptibility loci in different populations, single genes predisposing to the development of keloids have not been identified:

●Genetic linkage analysis studies identified keloid susceptibility loci on chromosome band 2q23 in a Japanese family, on chromosome band 7p11 in an African American family, and on chromosome bands 10q21.21 and 18q21 in Chinese Han families [25].

●A genome-wide association study in a Japanese population identified four single nucleotide polymorphisms across three loci (rs873549 at 1q41, rs940187 and rs1511412 at 3q22.3, and rs8032158 at 15p21.3) associated with keloid formation, one of which (rs8032158) was located within the intron of the NEDD4 gene, encoding a neural precursor cell expressed developmentally down-regulated protein 4 [26].

●A study of human leukocyte antigen (HLA) polymorphisms found a positive association with keloids and HLA-DRB1*15 in a United Kingdom cohort [27]. Another study found a positive association of HLA-DQA1*0104, DQB1*0501, and DQB1*0503 with keloids in a Chinese Han cohort [28].

Some genetic disorders are also associated with a high susceptibility to keloids. One example is Rubinstein-Taybi syndrome, a microdeletion syndrome characterized by growth restriction, microcephaly, dysmorphic features, broad thumbs and toes, intellectual disability, and increased frequency of keloid development either spontaneously or following minor trauma [29]. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '16p13.3 deletion syndrome (Rubinstein-Taybi syndrome)'.)

Other factors — Patient-related factors that have been associated with an increased risk of developing keloids include young age, pregnancy, and hypertension:

●Age – Young age is associated with an increased risk of keloid development, with a peak incidence in the second and third decades of life, suggesting that hormonal factors associated with puberty may play a role. In a series of 304 pediatric patients with keloids, the mean age at onset was 9.3 years (range 3 months to 18 years) [30]. In a Japanese series of 1290 patients with keloids aged 0 to 78 years, the reported median age at onset was 16 years for males and 20 years for females [31]. Similarly, in a Chinese series of 715 patients with keloids, the mean age at onset was 21 years in females and 22.6 years in males [32].

●Pregnancy – There are several reports of worsening of keloids during pregnancy [33,34]. It has been suggested that increased estrogen levels may promote keloid growth.

●Hypertension – Hypertension may be associated with both the development of keloids and hypertrophic scars and their clinical severity [35-37]. This may reflect the damaging effect of hypertension on vascular endothelium. This damage includes hyperpermeability, which could promote the abnormal influx of inflammatory factors and cells into the wound/scar bed, thus worsening the local inflammation [9,37].

CLINICAL PRESENTATION — Hypertrophic scars and keloids present clinically as indurated, elevated, erythematous lesions with a glossy surface, red in color in White individuals (picture 1) or violaceous-black in Black individuals (picture 2A-B). Clinically, keloids and hypertrophic scars are broadly distinguished by their growth pattern, with horizontal growth beyond the margins of the original wound being the defining characteristic of keloids (table 1) [38,39]. Moreover, while a hypertrophic scar eventually reaches a growth plateau that is generally followed by a regression phase, keloids show a continued growth.

Hypertrophic scars become obvious within weeks of injury. In patients with minor or absent risk factors for pathologic scarring, these lesions generally grow for three to six months, enter a plateau phase, and then start to regress. However, if risk factors for abnormal scarring are strong (eg, stretching), they will keep growing. Typical examples are scars located on a joint after orthopedic surgery. Due to exercise of the joint during rehabilitation, these scars often grow vigorously and can result in contractures that require reconstructive surgery.

Hypertrophic scars can be linear in shape (eg, surgical scars) or diffuse (eg, burn scars). Keloids can have a nodular shape (picture 2B), a butterfly shape, or a mushroom or cauliflower shape (picture 3A-B), depending on the body site and eliciting factors (eg, trauma, surgery, piercing practices, infection).

The most important subjective symptoms of keloids are pain and itching, which are usually more prominent in keloids than in hypertrophic scars. Persisting pain may be uncommonly due to an inflamed epidermal cyst arising in the scar tissue [40].

PATHOLOGY — The reticular dermal layer of pathologic scars displays chronic inflammation, marked angiogenesis, and large amounts of collagen [41]. Keloids can often be distinguished from hypertrophic scars on histopathology. Keloids contain thick bands of hyalinized collagen (keloidal collagen), whereas hypertrophic scars bear collagen nodules. However, many scars present both of these histopathologic features [42]. This observation is consistent with the concept that hypertrophic scars and keloids are extreme manifestations of the pathologic scarring spectrum.

DIAGNOSIS — The diagnosis of hypertrophic scars and keloids is based on clinical features and history in most cases (see 'Clinical presentation' above). A lesion biopsy may be necessary if the diagnosis is uncertain.

History focuses on the identification of the cause of the pathologic scar. While most pathologic scars result from a nonsuperficial wound, either surgical or traumatic, keloids can arise from negligible wounds that may have gone unnoticed by the patient. In such cases, it is important to question the patient about conditions or events that occurred in the months preceding the scar development.

Distinguishing hypertrophic scars from keloids — In some cases, distinguishing hypertrophic scars from keloids may be difficult either clinically or pathologically. The Japan Scar Workshop (JSW) 2015 Scar Scale (JSS 2015) is a simple tool proposed to aid clinicians in distinguishing hypertrophic scars from keloids and assessing their severity [43,44]. The scale includes information on 12 variables, including demographics, etiology, location, clinical features, and subjective symptoms, each of which is assigned a score of 0 to 3. A JSS 2015 overall score of 6 to 15 points indicates that the lesion has definite characteristics of a hypertrophic scar and will respond well to treatment. In contrast, a JSS 2015 score of ≥16 points indicates that the lesion has definite keloid characteristics and will tend to resist treatment. Scores <6 points indicate mature scars.

DIFFERENTIAL DIAGNOSIS — Benign and malignant cutaneous tumors and other proliferative lesions may rarely be misdiagnosed as keloids [45]. A lesion biopsy and histopathologic examination usually lead to the correct diagnosis.

Lesions that clinically mimic keloids include:

●Mixed tumor of the skin (chondroid syringoma) (picture 4) (see "Cutaneous adnexal tumors")

●Dermatofibrosarcoma protuberans (picture 5) (see "Dermatofibrosarcoma protuberans: Epidemiology, pathogenesis, clinical presentation, diagnosis, and staging")

●Cutaneous squamous cell carcinoma (picture 6) (see "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis")

●Juvenile xanthogranuloma (picture 7) (see "Juvenile xanthogranuloma (JXG)")

●Pseudolymphoma (picture 8) (see "Cutaneous B cell pseudolymphoma" and "Cutaneous T cell pseudolymphomas")

●Nodular scleroderma (picture 9), also called keloidal scleroderma or keloidal morphea (see "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults")

●Lobomycosis (picture 10), a chronic fungal infection of the skin and subcutaneous tissue occurring in tropical areas of Latin America (see "Lobomycosis")

PREVENTION

Promoting fast wound healing

Wounds not caused by burn or surgery — In general, it is important to promote rapid wound healing. The risk of developing a hypertrophic scar or keloid increases when the healing time is longer than three weeks. This can be achieved by keeping the wound clean and moisturized, thereby ensuring that the time to re-epithelialization is as short as possible. The wound should also be fixed (eg, with paper tape) to avoid strong tension on the wound. If a new scar shows any signs of ongoing or relapsing inflammation (eg, appearance of small indurations), topical corticosteroids that dampen the inflammation should be started as soon as possible and maintained until the induration has resolved. Steroid tape/plaster is particularly effective in this situation [3,46].

Burn wounds — The prevention and management of keloids and hypertrophic scars due to burn injuries are discussed separately. (See "Hypertrophic scarring and keloids following burn injuries".)

Surgical incision and repair techniques — To prevent the pathologic scarring of surgical incision wounds, several preoperative, intraoperative, and postoperative precautions should be taken [47]:

●Linear incisions should not run in the direction of prevailing skin tension. For example, horizontal incisions are better for the abdomen than vertical incisions because the tensile direction in this region is vertical. Because a healing wound is initially stiff due to the immature collagen deposits, a linear surgical scar acts like a hard string. Repeated stretching due to body movements generates high tension forces in the scar bed, preventing its relaxation into the softer, healthy surrounding skin and inducing continued inflammation.

●If it is not possible to avoid placing linear incisions in the tensile direction, the surgeon should consider using Z-plasties, which break up the hard, string-like scar. In some cases, local flaps could be used to disrupt potential tension on a scar after surgery [47,48].

●During surgery, subcutaneous/fascial tensile reduction sutures should be used. These sutures allow close approximation of the wound edges. As a result, sutures can be placed without tension in the dermis, and the wound can then be closed with equally tension-free, superficial sutures [41,47,48]. We typically use nonabsorbable sutures. Whether the use of absorbable or nonabsorbable sutures influences the risk of hypertrophic scar development is uncertain [49,50].

Scar fixation — After surgery, wounds and the subsequent immature scars should be fixed. A variety of materials (including paper tape and silicone sheeting) are available, and all have shown some efficacy in preventing pathologic scarring:

●In a small, randomized trial evaluating the efficacy of paper tape application to support cesarean section wounds versus no treatment, the risk of developing a hypertrophic scar was nearly 14-fold greater in the no treatment group than in the paper tape group [51].

●In a 2013 Cochrane review, the use of silicone gel sheeting reduced the incidence of hypertrophic scarring in people prone to abnormal scarring (risk ratio [RR] 0.46, 95% CI 0.21-0.98) [52]. However, the included studies were deemed to be at high risk of bias.

A small, randomized trial also showed that surgical wounds on body regions that are highly prone to pathologic scarring (eg, Pfannenstiel and sternotomy wounds) may benefit from pre-emptive use of a topical corticosteroid [53].

Patient education — It is important to educate patients about the importance of avoiding stretching of the immature scar to prevent scar inflammation and overgrowth. Patients should thus be instructed to avoid activities that may apply stretching forces to their immature scars. Stabilization for three to six months is recommended in high-tension areas (eg, chest, abdomen) in patients at high risk of developing keloids.

Patients with surgical or trauma wounds are also counseled to avoid hot baths, which could aggravate surgery-induced inflammation [54,55]. Moreover, we advise patients who are prone to keloidal scarring to avoid body piercings. (See "Body piercing in adolescents and young adults".)

Adolescents with acne and a tendency to form keloids should seek early, appropriate acne treatment, which greatly increases the chance of scar-free healing. (See "Acne vulgaris: Overview of management".)

TREATMENT OF HYPERTROPHIC SCARS — Given their relative lack of aggressive behavior, many hypertrophic scars can be successfully treated conservatively. Surgery is usually reserved for scars causing joint contractures. Our approach to the treatment of hypertrophic scars is illustrated in the algorithm (algorithm 1) [3].

Conservative therapies — Conservative therapies are first-line treatments for hypertrophic scars. They include topical or intralesional corticosteroids, compression therapy, and gel sheeting [56].

Corticosteroid tape/plaster, injection, and ointment

●Corticosteroid tape/plasters – Corticosteroid tape/plaster is our preferred first-line therapy for small/moderate hypertrophic scars that do not cause contractures (picture 11) [44]. It is easy to use, painless, and suitable for use in pediatric patients. Tape/plaster is cut to match the scar shape, with minimal overlap with normal skin, and applied to the scar. It should initially be used continuously for at least three months, changing it every 24 to 48 hours.

Flurandrenolide (fludroxycortide) tape 4 mcg/cm², a high-potency topical corticosteroid (table 2), is available in the United States, Brazil, the United Kingdom, and other European countries. Plasters with deprodone propionate (a high-potency corticosteroid) are only available in Japan.

In our experience, most children with small hypertrophic scars will respond to fludroxycortide (flurandrenolide) tape. In an observational study of 30 adults and 30 children with hypertrophic and keloid scars, treatment with flurandrenolide tape for one year induced clinical scar improvement in 80 percent of children and only 20 percent of adults [57]. However, in adult patients, we prefer using deprodone propionate plaster [57]. The tape/plaster is most effective when used as soon as the slightest sign of scar inflammation appears [44].

●Intralesional corticosteroids – Intralesional corticosteroid injections are effective in inducing regression of small to moderate-size hypertrophic scars [58-61]. They reduce inflammation and promote collagen degradation. International guidelines recommend using triamcinolone 2.5 to 10 mg/site for scar management [62]. Injections can be repeated at one-month intervals.

A major drawback of intralesional corticosteroid injection is that it can be very painful. To reduce pain, we recommend avoiding injecting the solid, central part of the lesion. Instead, the needle should be inserted into the skin border between the lesion base and the normal skin [44]. In our experience, it is also better to first treat the lesion with corticosteroid tape/plaster (which is painless) before using corticosteroid injection because the tape/plaster will soften the scar and make the injection less painful.

Local and systemic adverse effects of triamcinolone injections include thinning/atrophy of the skin or subcutaneous tissues, steroid acne, capillary dilatation, hypopigmentation, Cushing syndrome [63], cataracts, and glaucoma. (See "Intralesional corticosteroid injection".)

●Topical corticosteroids – Corticosteroid ointments/creams may also be useful for small/moderate hypertrophic scars, although there are few studies on these agents. However, a major drawback is that they must be applied four times per day to achieve the same outcome as steroid tape/plaster [64].

Compression therapy — Compression therapy has long been a mainstay treatment for established hypertrophic scars. It is usually performed with pressure garments, bandages, or special devices for certain locations (eg, the ear). However, the evidence supporting the use of pressure therapy is limited and conflicting:

●A 2009 meta-analysis of six high-quality, randomized trials including 316 burn patients did not demonstrate a difference in the global scar assessment, pigmentation, vascularity, pliability, and color between patients treated with pressure garments and untreated patients [65]. However, pressure garment therapy reduced scar height, though the difference was small and likely of little clinical significance (standardized mean difference [SMD] -0.31, 95% CI -0.63 to 0).

●A 2017 meta-analysis of 12 studies (710 patients) found that pressure therapy (15 to 25 mmHg) significantly reduced the Vancouver Scar Scale score (mean difference -0.58, 95% CI -0.78 to -0.37), scar thickness (SMD -0.38, 95% CI -0.63 to -0.12), redness, pigmentation, and hardness [66].

Gel sheeting — The beneficial effects of silicone and nonsilicone sheets may reflect their ability to stabilize and moisturize the scar, thus decreasing inflammation [67]. It is important to educate patients on how to use these sheets properly [68]. A disadvantage of these sheets is that they fall off quickly in high temperatures due to sweating.

There is no difference in the effect depending on the material. The mechanism is to reduce tension. Gel sheets are generally removed and cleaned daily. They can be reused after washing until the adhesive material has disappeared.

A 2021 Cochrane review of 13 studies with 468 participants concluded that there is limited evidence from high-quality trials about the clinical efficacy of silicone sheeting in the treatment of hypertrophic scars [69]. Based on two studies with 31 participants (32 scars) reporting the severity of scarring assessed by health professionals using the Vancouver Scar Scale (score 0 to 15), the scar severity in the intervention group was 1.83 points lower than in the control group (mean difference -1.83, 95% CI -3.77 to 0.12, very low certainty evidence).

Two small, randomized trials suggest that there is no difference in the efficacy of silicone sheets compared with nonsilicone gel sheets or silicone gel [70,71].

Surgery — Small and/or linear hypertrophic scars can be resected completely in patients who desire cosmetic improvement. If contractures have developed, they should be released to improve joint function (algorithm 1). Surgery on hypertrophic scars should employ tension-releasing techniques, such as Z-plasty (picture 12), W-plasty, or local flap methods, as well as subcutaneous/fascial tensile reduction sutures [44,47,48].

Other therapies — Several other treatment options have been used for both hypertrophic scars and keloids:

●Laser therapy – Main indications for laser treatment of hypertrophic scars include persistent erythema, inflammation, and pruritus following conservative therapies [72]. (See "Laser therapy for hypertrophic scars and keloids".)

585 or 595 nm pulsed dye laser, 532 or 1064 nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, and carbon dioxide (CO₂) ablative fractional laser have been used alone or in combination for the treatment of hypertrophic scars due to their ability to disrupt the blood vessels, thereby preventing the influx of inflammatory cells and factors [73-83]. Ablative fractional lasers have also been used for transdermal delivery of drugs (eg, corticosteroids, fluorouracil, bleomycin) with inconsistent results [84-87].

The use of lasers for the treatment of hypertrophic scars and keloids is discussed in detail separately. (See "Laser therapy for hypertrophic scars and keloids" and "Overview of lasers in burns and burn reconstruction".)

●Cryotherapy – Several reviews suggest that intralesional, spray, or direct contact cryotherapy is safe and may effectively reduce hypertrophic scars and keloids, especially when combined with triamcinolone injections [59,88-94]. However, cryotherapy is painful and associated with risk of depigmentation and high recurrence rates [95].

●Scar massage – There is little evidence to support the benefit of this approach to reduce hypertrophic scars [96,97]. Moreover, given the potentially strong role of local tension in hypertrophic scar pathogenesis, it is possible that massaging a hypertrophic scar when it is still highly inflamed will worsen it.

●Intralesional agents – Other effective agents for both hypertrophic scars and keloids include intralesional injections with chemotherapeutic drugs (fluorouracil and bleomycin) or botulinum toxin type A [58,61,98-102]. These drugs probably act by dampening fibroblast activity and scar tension. (See 'Intralesional chemotherapeutic agents' below.)

Combining these drugs with intralesional triamcinolone appears to have superior effects compared with individual agents alone [61]. As an example, triamcinolone 2 to 10 mg/mL can be combined with low-dose fluorouracil (1.5 to 5 mg/mL) and injected at four-week intervals for a few months [103]. Low-dose fluorouracil is preferred to higher doses (40 to 50 mg/mL) to prevent local adverse effects (eg, skin necrosis, ulceration) as well as systemic toxicity.

Intralesional injections of the calcium channel blocker verapamil seem to be as effective as intralesional triamcinolone for the treatment of hypertrophic scars and keloids [61,102]. Verapamil may act by inhibiting fibroblast activity [104].

●Topical agents – Limited, anecdotal evidence suggests that topical application of nonsteroidal anti-inflammatory drugs (NSAIDs), onion extract gel [105-107], and mugwort lotion may improve hypertrophic scars [108].

●Oral tranilast – Tranilast, an antiallergic drug that inhibits transforming growth factor (TGF)-beta-1, may reduce subjective symptoms by suppressing scar inflammation [109].

●Adipose tissue transplantation – There is growing evidence that suggests that adipose tissue transplantation could promote wound healing and scar maturation. However, more clinical research is required before adipose tissue transplantation can be routinely used [110-112].

TREATMENT OF KELOIDS

Approach — The first step in the management of keloids is determining the severity of keloid disease and whether the lesion(s) will respond to conservative treatment (algorithm 2). The presence of one small/moderately sized keloid or several small keloids suggests a relatively weak keloid predisposition, which may be largely shaped by poor, local conditions [3,113]. These small keloids are likely to respond to conservative therapy. By contrast, the presence of a large and thick keloid or multiple large keloids, especially if they are on different body regions, indicates a strong keloid constitution that is dominated by genetic and/or systemic factors. These lesions will require a more aggressive approach, such as surgery followed by postoperative radiotherapy and conservative adjuvant measures.

Setting treatment goals — Before committing to a treatment regimen, it is essential to discuss with the patient the treatment options and set treatment goals. This is especially important for patients with large or multiple keloids. The main goals of treatment are reducing inflammation, improving the esthetic appearance, and preventing recurrence.

Small/moderate size single keloids — Small to moderate size keloids (<20 cm²) are treated in most cases with conservative therapies, including intralesional injection of corticosteroids, corticosteroid tape/plaster, or intralesional chemotherapeutic agents (algorithm 2) [44].

Corticosteroid injection, tape/plaster, and ointment — For small single keloids, we suggest intralesional injection of corticosteroids with or without intralesional injections of chemotherapeutic agents or corticosteroid tape/plaster rather than surgical excision as first-line therapy:

●Intralesional corticosteroids – Intralesional corticosteroid injections are preferred or used in combination with tape/plaster for small keloids (eg, earlobe keloids) that exhibit rapid growth (eg, growth visually noted by the patient in three months). We typically use triamcinolone acetonide 5 to 10 mg combined with a local anesthetic and inject using thin needles (30 or 27 G) and syringes with lock [47].

The injection should initially target the keloid border rather than the hard scar center. Once the scar has softened, subsequent injections can be done into the lesion center. Injections can be repeated at intervals of three to four weeks until the keloid has flattened. (See "Intralesional corticosteroid injection".)

Intralesional corticosteroids can be effective as monotherapy for small keloids [58,59,98,114]. However, their efficacy may be heightened by the combination with other agents, such as topical fluorouracil or botulinum toxin A [58,98,114]. (See 'Intralesional chemotherapeutic agents' below.)

●Tape/plaster – Unlike steroid injections, steroid tapes/plasters are painless, easy to use, and suitable for use in children. Flurandrenolide (fludroxycortide) tape 4 mcg/cm², a superpotent topical corticosteroid (table 2), is available in the United States, Brazil, the United Kingdom, and other European countries. Plasters with deprodone propionate (a high-potency corticosteroid) are only available in Japan.

Tape/plaster is cut to match the scar shape, with minimal overlap with normal skin, and applied to the scar. It should initially be used continuously for at least three months, changing it every 24 to 48 hours. If continuously applied for 3 to 12 months, corticosteroid tape/plaster as monotherapy can lead to resolution or considerable improvement of small keloids (picture 13). In addition, they are highly effective in extinguishing nascent recurrences after other methods, including surgery, have eliminated the lesion [3,47,64].

●Topical corticosteroids – There is very limited evidence that high-potency topical corticosteroid ointment/cream can effectively treat small keloids, especially when combined with laser therapy [84,115,116]. Topical corticosteroids must be applied multiple times per day, which limits their utility [3,47,64].

Intralesional chemotherapeutic agents — There is a large body of evidence that shows that fluorouracil injections effectively treat small or moderate-size keloids and prevent recurrence after surgery, especially when combined with triamcinolone injections [61,114,117,118]. Low-dose fluorouracil (1.5 to 5 mg/mL) can be combined with triamcinolone 2 to 10 mg/mL and injected at four-week intervals for a few months [103]. Low-dose fluorouracil is preferred to higher doses (40 to 50 mg/mL) to prevent local adverse effects (eg, keloid necrosis, ulceration) as well as systemic toxicity.

Bleomycin injections, with or without triamcinolone, are also effective for keloid treatment [101,102]. Bleomycin concentrations of 1.5 international units/mL or 1 mg/mL have been used, with injected doses of 0.25 mL/cm² to up to a maximum of 2 mL/cm² of skin treated [119,120]. Adverse effects of bleomycin include pain, superficial ulceration and crusting, hyperpigmentation, and dermal atrophy.

In a large, retrospective study, 314 patients with keloids were treated with shave excision followed after re-epithelization by monthly injections of bleomycin until resolution of the keloid, pain, and itching [121]. Complete flattening was noted in 87 percent of patients, with no recurrences at two years post-treatment.

Surgical excision plus postoperative adjuvant therapy — Small keloids can be completely excised in patients who prefer surgery for cosmetic concerns. However, as surgery alone is associated with a very high risk of recurrence (up to 100 percent), surgical excision should always be combined with postoperative adjuvant therapies, including radiation therapy (in adult patients only), intralesional corticosteroids, or corticosteroid tape/plaster. (See 'Postoperative radiation therapy' below and 'Intralesional chemotherapeutic agents' above and 'Corticosteroid injection, tape/plaster, and ointment' above.)

Large/multiple keloids

Surgical excision/volume reduction plus postoperative adjuvant therapy — For large or multiple keloids, the goals of surgery are [3,47]:

●Resecting whole keloid(s) if feasible

●Reducing the thick and hard areas and/or the number of keloids with partial excision

●Disrupting the tension on the scar with flaps

Because surgery alone is associated with an extremely high recurrence rate (up to 100 percent) [62], in adult patients, surgery must be followed by radiation therapy and thereafter by long-term tape fixation of the scar. (See 'Postoperative radiation therapy' below.)

As for hypertrophic scars, all surgical resections should be performed with techniques that diminish the tension on the dermis, including subcutaneous/fascial tensile reduction sutures [20,122], Z-plasties [123-125], and/or local flap transfer (picture 14A-B) [126]. Skin-pedicled flaps are superior to skin grafts because the latter do not expand after surgery and can result in circular, pathologic scars around the graft.

Flap surgery should be followed by multimodal therapy (ie, radiation therapy, tape fixation, and corticosteroid tape/plaster) at the donor site as well as the recipient site to prevent new keloid formation [126]. (See 'Prevention' above.)

Specific anatomic regions may require special techniques. As an example, the ball-like keloids that form on the earlobe (picture 3A) can be removed with wedge excision and primary closure [127]. Keloids on the cartilaginous part of the auricle or on the digits can be resected with core excision, which is where the dermal core of the keloid is removed but the overlying tissue is retained and then closed (picture 15A-B) [44,128-131].

A close clinical follow-up is warranted for these patients. If any signs of recurrence (eg, scar induration) are noted, the simple tape should immediately be replaced with steroid tape/plaster and, if necessary, intralesional injections of triamcinolone or chemotherapeutic agents.

Postoperative radiation therapy

General considerations — In adult patients, radiation therapy is essential after keloid surgery because it reduces the formation of blood vessels and suppresses the inflammation in the incisional wound [9], thus allowing the healing process to progress smoothly to completion. Postoperative radiation therapy is strictly contraindicated in pediatric cases. Keloids in children should be treated with conservative measures until adulthood.

While the radiation source used to be superficial or orthovoltage x-rays (photons) [132,133], electron-beam (beta-ray) is now often preferred because it exposes the internal organs to less radiation [47,124,134]. High-dose rate brachytherapy could also be an option, but its long-term safety remains to be determined [135-137].

Although there have been concerns that postoperative radiation could induce malignant tumors, there are extremely few reports of cancers associated with radiation therapy for keloids [130]. Moreover, these cases mostly involved high doses and/or pediatric cases, and the causal relationship was often unclear. Nonetheless, all patients who undergo postoperative radiotherapy should be followed up in the very long term.

Surgeons who are concerned about using postoperative radiotherapy to treat keloids should consult with radiation oncologists. Notably, a survey of European radiation oncologists from 1348 institutions showed that 90 percent accepted the notion of treating keloids with radiotherapy [138].

Our approach — Our approach to postoperative radiation therapy is as follows:

●Sites at high risk of recurrence – To maximize safety while still achieving good response rates, the author's institution postoperatively treats keloids on high-recurrence sites (eg, anterior chest, upper back/shoulder, suprapubic area) with 18 Gy/three fractions/three days, which delivers a maximal biologically effective dose (BED) of approximately 30 Gy. The BED, which is more important than the total dose, is calculated on the basis of the total dose, the number of fractions, and a tissue-specific constant that represents the cell survival curve in response to radiotherapy [139]. BEDs above this threshold are not recommended because they would elevate the risk of secondary carcinogenesis without increasing the benefit.

●Sites at low/intermediate risk of recurrence – Based on the author's dose optimization research, less susceptible sites can be treated with lower radiation doses [47,124]. Body sites with low susceptibility to recurrence (eg, earlobe) are treated with 8 Gy/one fraction/one day, while all other areas that are considered at intermediate risk of recurrence are treated with 15 Gy/two fractions/two days.

Several studies support the efficacy and safety of postoperative superficial radiation therapy for the prevention of keloid recurrence:

●In a series of 494 keloids treated at the author's institution between 2013 and 2017 with the modified protocols described above, the overall recurrence rate was 9.3 percent [124]. It should be noted that the author's institution classified even tiny indurations that trigger steroid tape/plaster treatment as recurrences.

●A meta-analysis of 72 studies, 80 percent of which were published before 2010, reported an overall recurrence rate of 22 percent for surgery plus postoperative radiation therapy [140].

●In a retrospective study of 61 patients with 96 keloids treated with superficial radiation therapy using a BED of 30 Gy within the first two days of surgery, the recurrence rate was 10.4 percent at 12 months and 12.7 percent at 18 months [141].

Primary radiation therapy — Radiation therapy has also been used as monotherapy to treat keloids. Although less effective than surgery with postoperative radiotherapy [140], the author occasionally uses it in older patients or patients with very large keloids because it immediately improves subjective symptoms (eg, pain, itching). It also causes the color and thickness of the scars to progressively normalize over the next 12 months [2]. The total radiation dose tends to be higher than that used in postoperative radiation.

Laser therapy — Laser therapy for keloids is discussed separately. (See "Laser therapy for hypertrophic scars and keloids".)

PROGNOSIS — Worsening of keloids and hypertrophic scars is associated with puberty, higher levels of physical activity (eg, in athletes), and pregnancy in females. The lesions often improve when people reach their 50s and their skin tension drops significantly.

FOLLOW-UP — Patients who have been treated for keloids or hypertrophic scars should be followed up closely, at least every three months for at least 18 to 24 months to allow for early detection and treatment of small recurrences that may respond well to steroid tape/plaster or injection. The follow-up can stop when the scar is flat and soft. The follow-up visits also represent an opportunity for educating patients about wound and scar management. (See 'Patient education' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Keloids and hypertrophic scars".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Keloids (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition and pathogenesis – Keloids and hypertrophic scars are dermal fibroproliferative disorders that result from aberrant wound healing due to persistent inflammation in the reticular dermis rather than autonomous cell proliferation. Genetic, systemic, and local factors contribute to pathologic scar formation in predisposed individuals. (See 'Etiology and pathogenesis' above.)

●Clinical features – Hypertrophic scars and keloids present clinically as indurated, elevated, erythematous lesions with a glossy surface, red in color in White individuals (picture 1) or violaceous-black in Black individuals (picture 2A-B). While hypertrophic scars do not exceed the margins of the original wound, keloids are characterized by continuous growth and invasion into the adjacent, healthy skin beyond the original wound boundary. (See 'Clinical presentation' above.)

●Prevention – Key factors to prevent keloids and hypertrophic scars include promoting rapid wound healing by keeping the wound clean and moisturized, fixing the wound with paper tape to reduce tension, and reducing inflammation at an early stage during the wound healing process. For surgical wounds, it is important that surgical incision be performed along lines of low skin tension, if feasible, and that suturing techniques aimed at reducing tension on the scar (eg, Z-plasties) be used. (See 'Prevention' above.)

●Treatment of hypertrophic scars – Our approach to the management of hypertrophic scars is illustrated in the algorithm (algorithm 1):

•Small/moderate size hypertrophic scars – For hypertrophic scars of small/moderate size that do not cause joint contractures, we suggest corticosteroid tape/plaster or intralesional corticosteroid injections rather than other conservative therapies (eg, compression therapy, gel sheeting) (picture 11) (Grade 2C). We prefer corticosteroid tape/plaster over intralesional corticosteroid injection or corticosteroid ointments.

Flurandrenolide (fludroxycortide) tape 4 mcg/cm², a superpotent topical corticosteroid (table 2), is available in the United States, Brazil, the United Kingdom, and other European countries. Plasters with deprodone propionate (a high-potency corticosteroid) are only available in Japan.

Tape/plaster cut to match the scar shape is used continuously for at least three months, changing it every 24 to 48 hours. (See 'Conservative therapies' above.)

Large hypertrophic scars – For large hypertrophic scars and scars that cause severe joint contractures, treatment options include surgical excision or partial surgical contracture release. Depending on a scar's size and location, tension-releasing surgical techniques, such as Z-plasty (picture 12), W-plasty, or local flap methods, should be employed. Laser therapy for hypertrophic scars and keloids is discussed separately. (See 'Surgery' above and "Laser therapy for hypertrophic scars and keloids".)

●Treatment of keloids – Our approach to the management of keloids is illustrated in the algorithm (algorithm 2):

•Small/single keloids – For patients with small single keloids (<20 cm²), we suggest conservative treatment with intralesional corticosteroids with or without intralesional chemotherapeutic agents (eg, fluorouracil, bleomycin) or corticosteroid tape/plaster rather than surgical excision (Grade 2C). Because intralesional injections are very painful, we prefer corticosteroid tape/plaster for very small keloids, especially in children. (See 'Small/moderate size single keloids' above.)

•Large/multiple keloids – For adult patients with large or multiple keloids, we suggest surgical excision/volume reduction followed by postoperative radiation therapy rather than surgical excision alone (Grade 2C). Postoperative radiation therapy is strictly contraindicated in children. (See 'Large/multiple keloids' above.)

●Follow-up – Patients who have been treated for keloids or hypertrophic scars should be followed up closely, at least every three months for at least 18 to 24 months to allow for early detection and treatment of small recurrences that may respond well to conservative therapy with corticosteroid tape/plaster or injection. (See 'Follow-up' above.)