Typically, wound healing occurs in a dynamic process of balanced regulation to form an as small and minimally visible scar as possible. When this regulation is unbalanced, less desirable scars occur such as hypertrophic scars and keloids. Hypertrophic scars and keloids are both raised, firm scars formed from excess fibrinogen production of collagen during healing. They can both be symptomatic, most commonly pruritic but can also be painful, and can cause movement restrictions and cosmetic disfigurement. Although these may often be confused, there are distinct differences between the two. Hypertrophic scars are contained within the site of injury and may regress over time while keloids spread beyond the borders of the initial injury and do not regress. On histological examination, hypertrophic scars tend to have collagen in a wavy, regular pattern, whereas keloids have no distinct pattern of collagen.
Hypertrophic scars and keloids arise from some injury or irritation to the skin that goes deep enough to affect the dermal layer. They can occur after burns, surgery, insect bites, tattoos, acne or chicken pox and piercings. Although the cause remains unknown, there are several associations thought to influence the formation of these scars. There is evidence to suggest that any condition that increases systemic inflammation can increase the risks of hypertrophic scars and keloids. Some have suggested that sex hormones may affect keloid production by increasing inflammation leading to overproduction of collagen. Others have also seen in an increase in number and size of keloids in people with hypertension.
Keloid formation seems to have a genetic predisposition. Keloids typically form in higher rates in people with darker skin complexion than individuals with a fairer complexion. The highest prevalence is seen in the African population, followed by the Asian and Hispanic population and less frequently in Caucasians. Some studies have shown keloid formation in twins, suggesting a genetic predisposition, as well as several generations of families that are affected by keloid formation.
As opposed to keloids, hypertrophic scars do not appear to have a genetic predisposition. Some studies suggest, however, that they are more common in populations with a darker complexion. Hypertrophic scars also appear on areas of skin subject to stretching, due to the increased tension.Reports show that the incidence of forming hypertrophic scars is 39% to 68% after a surgical procedure and 33% to 91% after burns. Although there have been reports stating an increase in hypertrophic scarring in women, other studies have shown no difference between men and women.
Both keloids and hypertrophic scars tend to occur in younger populations, ages 11-30 years old, which is thought to be the result of the increased rate of epidermal turnover in this younger population and increased production of collagen. Younger populations are also thought to have more tension on their skin and a much more active immune system as opposed to older individuals with more elastic skin and decreased immune response.
In normal wound healing, there are three phases which include the inflammatory phase, proliferative phase, and a remodeling phase. The first inflammatory stage of healing may be most important in determining the outcome of the scar. It is during this phase that inflammation regulation takes place through proinflammatory cytokines, IL-6 and IL-8, and an anti-inflammatory cytokine, IL-10. A change in expression in these pro-inflammatory and anti-inflammatory cytokines may lead to an increased incidence of hypertrophic scar and keloid formation.
During the proliferative phase of healing, macrophages in the area of injury release growth factors, such as transforming growth factor beta (TGF-beta), which activates fibroblasts to create collagen. In hypertrophic scars and keloids, the thinking is that the dysregulation of TGF-beta leads to the formation of these types of scars. TGF-beta 1 and 2 manage activation of fibroblasts, while TGF-beta 3 is a receptor antagonist and leads to decreased fibroblast activity. The belief is that overexpression of TGF-beta 1 and 2 and decreased expression of TGF-beta 3 is what leads to increased extracellular matrix production causing these abnormal scars. There is a 3-fold increase of collagen production in hypertrophic scars and a 20-fold increase in keloids, leading to a larger, abnormal appearing scar.
In keloids, several histological findings can help to distinguish it from other types of scarring. For example, increased numbers of mast cells are present in keloid scar tissue compared with normal scar tissue. There is an increase in keratinocytes in the epidermis, which may account for the thicker epidermal layer seen in keloids. In normal dermal tissue, there are two distinct layers: the papillary and reticular layers. In keloid tissue, there is no distinction seen between these two layers. There is also an abundance of collagen in keloid tissue, arranged in a haphazard pattern, or whorls, as opposed to the parallel pattern seen in hypertrophic scars and normal scar tissue. There is an increased ratio of type I/III collagen in keloid cells when compared with normal skin tissue, but both types are present in greater quantities in keloid scar tissue when compared to normal tissue.
Histologically, hypertrophic scars classify as having a flattened epidermis with increased collagen fibers organized in a pattern parallel to the dermis. Blood vessels orient vertically, and there is papillary and reticular dermal scarring. Collagen fibers in hypertrophic scars are finer than in keloids, and there is a greater number of Type III collagen compared with type I collagen. As opposed to keloids, hypertrophic scars have myofibroblasts and alpha-smooth muscle actin.
Both keloids and hypertrophic scars have a raised, thickened scar with increased cellularity and increased collagen nodules. Keloids can appear after trauma or spontaneously and occur commonly in earlobes, shoulders, chest, back, cheeks, and knees. They most commonly appear in darker skin tones, and there is a strong genetic predisposition. They can be painful and often are pruritic. They appear around 3 months after an injury but continue to proliferate with no improvement. There is a high recurrence rate for keloids after attempted excision, and they are harder to treat than hypertrophic scars.
Hypertrophic scars have a higher incidence of occurrence compared with keloids and are differentiated by remaining confined to the original wound border. There is not a strong genetic predisposition as with keloids and can occur commonly in all skin tones. These frequently occur in extensor surfaces where there is increased tension. They can appear within one month of injury and begin regress after six months. If excised, hypertrophic scars have a decreased incidence of recurrence, making treatment easier than that of keloids.
The evaluation of a patient with a keloid or hypertrophic scar should begin with patient history. If there was no associated trauma, it is less likely a hypertrophic scar, as these are only posttraumatic. If there is a known injury, it may be either. Asking the patient if they experience pain or pruritus is important due to an increased incidence of pain and pruritus in keloids. Your history should also include a family history due to a strong genetic predisposition to keloid formation. Knowing how long a scar has been present and if there have been any changes in size can also help in your evaluation. If there is evidence that a scar is improving over time, it may indicate the patient has a hypertrophic scar as keloids do not regress.
On physical exam, the location of the scar is essential, as keloids are typically present on earlobes, face, chest, and back, whereas hypertrophic scars are more common on extensor surfaces. The patient's skin tone is also crucial because keloids are more common in darker skin tones and hypertrophic scars are present in all skin types. Keloids will grow beyond the borders of the initial injury or occur spontaneously, and hypertrophic scars remain contained within the area of injury.
Histological stain should also be used to evaluate the patient, as a more parallel pattern of collagen is characteristic of hypertrophic scars, and a random, whorl pattern of collagen is characteristic of keloids. Hypertrophic scars will contain thin collagen fibers with a greater ratio of collagen type III to type I and keloids will be predominantly thick fibers of type I collagen. Hypertrophic scars will have myofibroblasts and alpha-smooth muscle actin, which will both be absent in keloids.
Treatment of hypertrophic scars and keloids can be challenging, and there are several modalities available. The most important guideline for scarring is prevention by avoidance of any unnecessary procedures. When these procedures are unavoidable, it is important to add prophylactic therapies, such as topical therapies during wound healing to prevent the formation of an abnormal scar. However, many patients already have an injury that has formed a keloid, or hypertrophic scar and management of these patients is important to aid in the improvement of pain or pruritus as well as improving cosmetic outcomes.
First-line therapy of keloids and hypertrophic scarring includes occlusive dressings, compression therapy, and steroids. Occlusive dressings are thought to work by reducing collagen synthesis by decreased delivery of blood, oxygen, and nutrients to the scar. Patients must wear these dressings twenty-three hours a day, and they work best immediately after injury or surgery. Compression therapy is another treatment option which provides local pressure to the affected area; this has a thinning effect on the skin and reduces cohesiveness of the collagen fibers. Examples of compression therapy include button compression, for earlobe keloids, pressure earrings, ACE bandages, and spandex bandages. Steroids are also first-line and can be used alone or in conjunction with other therapies. Steroids decrease the synthesis of collagen and proinflammatory mediators. Intralesional triamcinolone injections are used every four to six weeks throughout several months as either monotherapy or as an adjuvant therapy to other treatments.
Surgical treatment includes excision of the scar by a full excision with primary closure or a shave excision with healing by secondary intention. Both procedures require post-operative compression dressings. Although there is a high recurrence of keloids with excision, with reduced recurrence when done in conjunction with steroids, radiotherapy and interferon therapy. Cryosurgery works by inducing cellular injury and necrosis to the affected area and reducing the area of the scar. Cryotherapy works better on smaller scars and has a decreased rate of recurrence when used on hypertrophic scars compared with keloids.
Radiation therapy is an option for keloids, primarily as an adjunct after surgical excision. Examples of radiation therapy are superficial x-ray, electron-beam therapy and brachytherapy, used primarily for severe keloids after surgical excision. Although the risk of malignancy from radiation therapy is rare, it is one disadvantage of radiation therapy.
Newer adjuvant and emerging therapies include interferon, 5-fluorouracil, imiquimod, tacrolimus, bleomycin, retinoic acid and botulinum toxin A. Interferon therapy works in vitro by reducing collagen synthesis. 5-Fluorouracil works as an antimetabolic agent by interrupting RNA, casuing inhibition of fibroblast proliferation and TGF-beta expression to decrease Type I collagen in scar tissue. In keloidal tissue, imiquimod causes induction of apoptotic genes causing cell death in these tissues. Tacrolimus is a topical treatment that leads to decreased fibroblast proliferation by downregulating TGF-beta receptors. Bleomycin is used in dermatology primarily to treat recalcitrant warts and keratoacanthomas but in vitro administration to fibroblasts has shown a decrease in collagen synthesis. Retinoids are inhibitors of matrix metalloproteinases which overexpress in keloids and hypertrophic scars. Tretinoin and isotretinoin, both retinoids, cause a reduction in collagen synthesis leading to improved scar appearance. Tension is thought to be a factor leading to the formation of keloids and hypertrophic scars. Botulinum toxin A is thought to reduce tension on the healing wound, leading to improvement in scarring.
Some malignant mimickers of keloids and hypertrophic scarring can include malignant dermatofibrosarcoma protuberans. This condition can be distinguished from keloids and hypertrophic scars by microscopy, showing a storiform pattern of spindle cells with a honeycombed pattern of fibrous stroma. They will contain vimentin, CD34, Bcl-2, HHF-35, and smooth muscle actin on immunohistochemistry, which are not present in keloids and hypertrophic scars. Trichilemmal carcinoma is another rare cutaneous adnexal malignant tumor that can resemble keloids. These come from hair follicles and are diagnosed by large, polygonal keratinocytes with clear, glossy periodic acid-Schiff-positive cytoplasm. Keloidal basal cell carcinoma can be confused with keloids and contains prominent, keloidal type thick collagen bundles. In another case, they misdiagnosed a 9-year-old with having a keloid that turned out to be a giant cell fibroblastoma, another malignant tumor. It is important to differentiate these malignancies from keloids or hypertrophic scars, especially before treatment, as steroids are contraindicated in malignant tumors, yet steroids are a common treatment for keloids and hypertrophic scars.
Cutaneous scleroderma often gets misdiagnosed as keloids or hypertrophic scarring, and careful consideration should be taken to diagnose cutaneous scleroderma correctly so as not miss a systemic disease. Cutaneous scleroderma presents with a thickened dermis and hyper-pigmented keloid like lesions. On microscopic exam, they find collagen bundles to lie parallel to the dermis with a decreased number of fibroblasts when compared with other scar tissues. Sclerotic neurofibroma may also be mistaken for a keloid; however, testing will reveal positive findings of protein S100. Infections such as a hair folliculitis can be confused for a keloid. Folliculitis can be bacterial or fungal, and it is important to distinguish infection from a keloid or hypertrophic scar as steroids are contraindicated in an infection.
Hypertrophic scarring has a good prognosis when compared with keloids. Hypertrophic scars typically develop soon after injury and may increase in size for a period before regressing on their own. They have a better response to treatment without recurrence and typically only require a single treatment modality.
As opposed to hypertrophic scars, keloids have a worse prognosis. Keloids tend to have a genetic component, and at-risk patients can develop multiple keloids from surgeries or injuries. Keloids can continue to develop for up to one year and do not spontaneously regress. After treatment, especially surgical excision, keloids have a high rate of recurrence, making treatment difficult. It is crucial that adjuvant therapies are incorporated after surgery to aid in the prevention of recurrence.
Keloids and hypertrophic scars can lead to prolonged pain and pruritus, are cosmetically disfiguring and can be functionally debilitating causing emotional and psychological distress to patients. There is an abundance of treatments available, but none are perfect, and they each have side effects of their own. Pruritus is the most common complication of keloids and hypertrophic scarring, followed by pain. Depending on location and size, these scars can cause movement restrictions to patients, and there is significant evidence proving a psychosocial aspect of scarring.
Treatments are also not without consequences. There is a risk of recurrence of keloids and hypertrophic scars with any therapy, with the highest recurrence rate following surgical excision of keloids. Steroids carry a risk of telangiectasias, atrophy and changes in pigmentation around the treatment site. Cryosurgery frequently causes hypopigmentation to the treatment area and can cause blisters and pain. Radiation therapy has a risk of malignancy although they have observed no cases of malignancy following radiation therapy for keloids and hypertrophic scarring.
Patients should receive education on the risk factors of keloids and hypertrophic scars. They should counsel those at risk for forming these scars before any surgical procedure on prevention and alternative forms of management. Although any injury or surgery can lead to a scar, the increased incidence of pain and pruritus, as well as the potential for functional disability, is much higher in keloids and hypertrophic scarring. Although there are several modalities of treatment available, there is no therapy that is completely effective in prevention and treatment of these scars. Especially with keloids, there is a high incidence of recurrence despite the method of treatment used. It is important for patients to work closely with a dermatologist to appropriately treat and manage these scars to prevent further enlargement and disability associated with keloids and hypertrophic scars.
Keloids and hypertrophic scars used to be diagnosed and managed by primary care physicians. However, with such a vast array of treatments available, dermatologists and possibly a plastic surgeon should be incorporated in treatment and management. Correct diagnosis is vital, so as not to miss a systemic disease or malignancy. A necessary diagnostic measure in differentiating these scars from other diagnosis is a biopsy. It may be important for a pathologist to review biopsy findings to come to a definite diagnosis.
If performing a surgical excision, having a surgeon that specializes in this area, such as a plastic surgeon, is vital to ensure the best outcome possible. There may also be a need for a wound nurse for management of pressure and occlusive dressings after surgery. Data proves that taking these measures after surgery leads to an improvement in size and decreased rates of recurrence. Treatments that involve radiation therapy may require a radiologist to aid in treatment and pharmacists are important in the proper dosing and prescribing for newer treatments involving 5-fluorouracil, interferon, bleomycin, and other adjuvant therapies. With this interdisciplinary approach and early, aggressive treatment, keloid, and hypertrophic scar formation may be prevented or significantly improved. (Level III)
|||Berman B,Maderal A,Raphael B, Keloids and Hypertrophic Scars: Pathophysiology, Classification, and Treatment. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2017 Jan [PubMed PMID: 27347634]|
|||Trace AP,Enos CW,Mantel A,Harvey VM, Keloids and Hypertrophic Scars: A Spectrum of Clinical Challenges. American journal of clinical dermatology. 2016 Jun [PubMed PMID: 26894654]|
|||Ogawa R, Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis. International journal of molecular sciences. 2017 Mar 10 [PubMed PMID: 28287424]|
|||Glass DA 2nd, Current Understanding of the Genetic Causes of Keloid Formation. The journal of investigative dermatology. Symposium proceedings. 2017 Oct [PubMed PMID: 28941494]|
|||Butzelaar L,Ulrich MM,Mink van der Molen AB,Niessen FB,Beelen RH, Currently known risk factors for hypertrophic skin scarring: A review. Journal of plastic, reconstructive [PubMed PMID: 26776348]|
|||Mahdavian Delavary B,van der Veer WM,Ferreira JA,Niessen FB, Formation of hypertrophic scars: evolution and susceptibility. Journal of plastic surgery and hand surgery. 2012 Apr [PubMed PMID: 22471257]|
|||Jumper N,Paus R,Bayat A, Functional histopathology of keloid disease. Histology and histopathology. 2015 Sep [PubMed PMID: 25900252]|
|||Arno AI,Gauglitz GG,Barret JP,Jeschke MG, Up-to-date approach to manage keloids and hypertrophic scars: a useful guide. Burns : journal of the International Society for Burn Injuries. 2014 Nov [PubMed PMID: 24767715]|
|||Nguyen CM,Burch JM,Fitzpatrick JE,Peterson SL,Weston WL, Giant cell fibroblastoma in a child misdiagnosed as a dermatofibroma. Pediatric dermatology. 2002 Jan-Feb [PubMed PMID: 11860566]|
|||Ogawa R,Akaishi S,Hyakusoku H, Differential and exclusive diagnosis of diseases that resemble keloids and hypertrophic scars. Annals of plastic surgery. 2009 Jun [PubMed PMID: 19461281]|
|||Ud-Din S,Bayat A, New insights on keloids, hypertrophic scars, and striae. Dermatologic clinics. 2014 Apr [PubMed PMID: 24680006]|