Are You Confident of the Diagnosis?
What you should be alert for in the history
Keloids and hypertophic scars are thought to be an exaggerated wound healing response after trauma, injury, or surgery of the skin. The most common history preceding keloid formation is injury or surgery of the skin, extending into the dermis. The incidence of keloid or hypertrophic scar formation after trauma or surgery has been estimated as high as 5%-15% . Less invasive procedures, such as ear piercing, may be the inciting cause, which can be discovered through astute questioning during the history and physical.
African-American, Asian, Hispanic, and Mediterranean ethnicities may be at increased risk for keloid and hypertrophic scar formation.
The phenomenon of spontaneous keloids has also been well described and is much less common . As the term implies, spontaneous keloid formation occurs de novo without a known eliciting cause such as surgery or injury to the skin. Some investigators believe that seemingly small and innocuous triggers of injury, such as an inflammatory acne papule, may be the underlying cause of spontaneous keloids.
A family history of keloid or hypertophic scar formation, along with a prior personal history of keloid formation, are pertinent clues to the diagnosis, as genetic susceptibility to this disorder is suspected as a contributing factor.
A patient history of chronic razor burn, consistent with pseudofolliculitis barbae, on the anterior bearded neck, or on the back of the neck along the hairline, may develop into acne keloidalis nuchae.
Small keloidal papules or nodules may be associated with chronic follicular trauma from ingrown hairs in individuals with extremely curly hair and neck hairs; the condition is particularly common in the African-American population. It is unknown whether or not this follicular reaction pattern predisposes a patient to keloids on other parts of the body.
Characteristic findings on physical examination
Both keloids and hypertrophic scars may appear as firm rubbery lesions or shiny fibrous nodules that may be flesh-colored to pink or even dark-red to brown (Figure 1, Figure 2, Figure 3, Figure 4) .
By definition, keloids are plaques or nodules that extend beyond the borders of the prior trauma or surgery, whereas hypertrophic scars are limited to the area of injury. Keloids more commonly demonstrate dysthesia, ranging from mild itching or tingling, to frank pain and severe pruritus at rest or with minimal tactile stimulation such as intermittent rubbing by clothes.
Frequently, keloids can be quite disfiguring, expanding far beyond the site of initiation and encompassing entire anatomic areas (such as the chest or beard). After burn injuries, large keloids may replace normal tissue, causing functional abnormalities of limbs if flexor or extensor joint surfaces are involved.
Expected results of diagnostic studies
No particular test is needed for diagnosing keloids or hypertophic scars. The combination of a clinical history of a trauma or surgery, along with the clinical appearance and associated dysthesia is usually sufficient for diagnosis; however, a skin biopsy for borderline lesions and lesions mimicking atypical infections or malignancies can readily demonstrate features consistent with keloids or hypertrophic scars (Figure 5).
The histopathology of keloids routinely shows large thick and frequently irregular whorled collagen fibers and fibroblasts within the reticular dermis and subcutaneous tissue. Hypertrophic scars display less profound collagen deposition with finer, randomly arranged collagen fibers and fibroblasts, with a higher percentage of vessels when compared to keloids, although the distinction can be subjective (Figure 6, Figure 7).
Ultrasound can demonstrate a homogenous and hyperdense cutaneous or subcutaneous mass, although no single feature identifies the mass uniquely as a keloid or hypertophic scar. More recently, multiphoton confocal microscopy of keloidal tissue has shown characteristic fibroblast-rich disorganized collagen fibers, arranged in complex swirls 20-30 microns in diameter. Normal tissue showed collagen fibers as distinct straight strands less than 10 microns in diameter. The differences were described as subtle, but apparent.
No serologic tests are readily available to either diagnose keloids and hypertrophic scars, or identify at-risk individuals.
Genetic studies to identify at-risk individuals are considered experimental and are not routinely available. Recently, four susceptibility loci on chromosomes 1, 3, and 15 have been uncovered in Japanese patients with keloids. These susceptibility loci were not seen in the controls, who did not have the disease.
The diagnosis of keloids or hypertrophic scars is essentially pinned on clinical data. As mentioned above, the combination of a clinical history of a preceding trauma or surgery, along with the clinical appearance and associated dysthesia are usually sufficient for diagnosis; however, a skin biopsy for borderline lesions and lesions mimicking atypical infections or malignancies can readily demonstrate features consistent with keloids or hypertrophic scars.
Spitting sutures or suture abscesses are a common cause of postoperative nodularity and hyperplastic growth in surgical wounds and scars. These changes frequently occur weeks to months after surgery. It is estimated that as many as one out of every twenty subcuticular sutures may “spit” or cause excess granulation tissue to protrude through the skin. This action often appears as a shiny red or purple nodule with focal tenderness or pruritus. Spitting sutures may express serosanguinous pus or spicules of partially degraded suture material that immediately decompress the nodule, differentiating it from a rubbery keloid.
Cutaneous sarcoidosis presents in 9%-37% of patients with systemic sarcoidosis, and may mimic keloids or hypertrophic scars. This granulomatous disease of unknown etiology most commonly affects the lungs and is more prevalent in African-Americans than in Caucasians.
The extent of skin lesions does not necessarily correlate with the extent of the systemic disease. Lesions are typically pink to yellowish-brown or purple, and on diascopy display a classic “apple jelly” appearance. Cutaneous sarcoidosis has a predilection to localize in scars or sites of injury, particularly those containing foreign material (e.g. splinters, suture material, or even silica). Topical or systemic steroids, plaquenil, or even surgical excision may be needed to treat extensive or disfiguring lesions.
Atypical mycobacterial infections are indolent slowly enlarging cutaneous and subcutaneous infections that can mimic keloids and hypertophic scars (Figure 5). They frequently occur after trauma or surgery, and acid-fast organisms such as Mycobacterium chelonae (subspecies abscessus) have been found in the tap water and gentian violet used by surgeons to mark patients preoperatively.
A high index of suspicion is needed to accurately diagnose and treat atypical mycobaterial infections, since the usual hallmarks of surgical site infections (pain, fever, worsening erythema, and a positive wound culture) may be absent. Routine beta lactam antibiotics are generally ineffective, and long-term treatment with a combination of clarithromycin, with or without surgical excision (if excision is feasible) may be required. Occasionally, oral rifampin may be added to enhance the efficacy of the antibiotic regimen.
Lobomycosis (keloidal blastomycosis) is a very rare tropical fungal infection found in South and Central America that affects the skin and subcutaneous tissue . It presents similarly to keloids or atypical mycobacteria. Exposure to aquatic environments and animals of the Amazon river basin, particularly fresh water dolphins, is the sine qua non element in the patient’s history that should raise suspicion. Lobomycosis is caused by Paracoccidioides (Glenosporella) loboi, which is abundant in the lesional tissue; this fungus is notoriously difficult to culture.
Certain cutaneous malignancies can also mimic keloids clinically. Dermatofibrosarcoma protuberans (DFSP) is a nodular cutaneous tumor that can mimic scar tissue or keloids. DFSP is a tumor of suspected fibroblastic origin that displays a storiform or cartwheel pattern on tissue biopsy. An adequate sampling depth down to the subcutaneous fat is crucial for differentiating DFSP from keloids or hypertophic scars, since DFSP will frequently fill the entire dermis and encroach the subcutis with an infiltrating pattern. Additionally, DFSP will routinely stain with CD34 to assist with diagnosis in histopathologically challenging cases.
Who is at Risk for Developing this Disease?
People of all ages are at risk for developing keloids, but toddlers and adolescents, as well as the elderly, are generally unaffected. Certain ethnicities are considered at increased risk, particularly African-American, Asian, Hispanic, and Mediterranean individuals. Many practitioners feel that the more darkly pigmented the skin of the patient, the higher the risk for keloid or hypertrophic scar formation. The incidence of keloid formation has been reported as high as 16% in black patient populations.
While prior injury is implicated for nearly all hypertrophic scars, some keloids may appear spontaneously without prior history. Comparatively, keloids can also have a much more delayed onset, ranging from weeks to months or years after injury to the skin. More innocuous forms of skin wounds, such as acne, burns, and pseudofolliculitis barbae, can also incite keloid formation in individuals who are prone to them.
Certain anatomic locations are more prone to keloid and hypertrophic scar formation: the earlobes, upper chest, upper back, deltoid region, and occasionally, the feet. Wounds in locations of relatively high tension (e.g. upper chest or back) are especially prone to keloid formation. Interestingly, a study in the 1960s demonstrated that keloids autotransplanted to areas of low tension subsequently resolved. Spontaneous resolution of keloids rarely happens but spontaneous resolution is not uncommon with hypertrophic scars.
What is the Cause of the Disease?
The cause of hypertrophic scars and keloids is not known, but is likely an amalgam of genetic predisposition, phenotypic presentation (skin color), and traumatic events (injury or surgery). After injury, the inflammatory phase of wound healing releases a cascade of cytokines. While complex, these cytokines ultimately result in a disorderly and increased production of collagen by fibroblasts and new dense blood vessel growth.
The key cell involved in hypertrophic scar or keloid formation has been termed the “keloid-derived fibroblast” (KF).
KFs have been shown to express and increase receptors for several keratinocyte-derived cytokines, including interleukin-1(IL-1), IL-6, transforming growth factor-beta, platelet-derived growth factor, and connective tissue growth factor.
Recently, the cytokine transforming growth factor beta-1 (TGF-β1) has been shown to regulate both collagen production and degradation in keloids and hypertrophic scars.
TGF-B1 and TGF-B2 are secreted by monocytes, macrophages, lymphocytes, and normal fibroblasts as precursor proteins after injury in wounds. In keloidal tissue, TGF-B1 causes an increase in type-1 collagen through activation of COL1 genes, but a decrease in matrix metalloproteinase-1 (MMP-1, interstitial collagenase); resulting in a net deposition of collagen and fibrosis.
Conversely, it has also been shown that TGF-B1 increases MMP-2 (gelatinase), allowing keloid fibroblasts to migrate 2.5 times faster than normal dermal fibroblasts. This may partially explain the proliferative and spreading nature of keloids over time.
Histologically, keloids display an increased blood vessel density when compared to normal dermis or normal scar tissue. The increase in the number of small irregular blood vessels in keloids and hypertrophic scars has been partially explained by a detectable upregulation of vascular endothelial growth factor (VEGF). Specifically, VEGF becomes elevated in keloids in response to TGF-B1. Bolstering this association are in vitro experiments showing that anti-TGF antibodies will decrease VEGF levels of cultured keloid fibroblasts, down to levels of normal tissue.
These cytokine abnormalities begin to explain what is both clinically and histologically seen: haphazard collagen deposition, increased blood vessels, and enlarged nodular scar tissue.
Systemic Implications and Complications
Hypertrophic scars and keloids alone do not predispose an individual to systemic disorders or complications; however, certain genodermatoses may present with an increased number of hypertrophic scars or keloids.
Keloids may be seen in Rubinstein-Taybi syndrome (beaked nose, widened phalanges of the thumbs and great toes, mental retardation), Goeminne syndrome (torticollis, cryptorchidism, renal dysplasia, multiple nevi), Ehlers-Danlos syndrome, and the third stage of yaws (caused by Treponemum pallidum pertenue).
silicone gels and sheeting
pressure dressings and pressure earrings
aggressive deep-tissue massage
pulsed dye laser
Optimal Therapeutic Approach for this Disease
The treatment approach to hypertrophic scars and keloids is based upon the severity of the lesion, prior history of the patient (“I am a keloid former”), and the willingness of the patient to undergo topical or invasive therapy. It is always best to use multiple modalities simultaneously to increase the chance of success and place some of the burden on the patient to get involved in his or her own care. It is also prudent to educate at-risk keloid-formers to avoid activities that may trigger other keloids to erupt such as piercings, tattoos, and aggressive shaving habits.
Topical therapies should be started early in treatment, but the expectations should be kept low. It is often stated that topical home therapy will slow down or halt the progression of a keloid, and in some instances, may decrease the size and symptoms of a keloid. This has been widely demonstrated in the rehabilitation of burn victims with large hypertrophic scars and keloids. Aggressive deep-tissue massage alone has been shown to soften and flatten (but not eliminate) such scars, allowing the patient to regain mobility after joint contractures were induced by keloid formation.
Commercially available acrylic pressure earrings are available that may be used for small ear keloids as monotherapy, or in conjunction with intralesional steroid injections (Figure 8). It is recommended that pressure earrings be used for several months, starting at the time of suture removal, if a keloid was surgically excised. Delascotm acrylic pressure earrings are one such affordable product that the patient or physician can order without custom fitting (www.delasco.com, product DPE-20/P).
The best evidence for the effectiveness of topical therapy exists for silicone sheeting and gels. These are FDA-approved products that can often be found over the counter in a local pharmacy (e.g. Dr. Blaine’s Scar Therapy) or purchased from a physician’s office.
A suggested regimen is applying the sticky product over the keloid for at least 12 hours a day for 12 weeks. Many patients note the biggest improvement in the first month of treatment; however, like most of these modalities, patients should be informed that despite flattening and increased pliability, the keloid will not likely completely vanish. Silicone should be used continuously between office visits, where more invasive therapies, such as intralesional steroid injections, are used periodically.
The mainstay of treatment for hypertrophic scars and keloids is periodic intralesional triamcinalone (ILT) injections. Some studies have quantified efficacy with ILT as roughly 85% . The injections should be started at monthly or 8-week intervals as soon as keloid formation is suspected. Some advocate starting ILT at the time of suture removal in known keloid or hypertrophic scar-formers. ILT concentrations of 10-20mg/cc are routinely used.
Total dosages not exceeding 80mg are routinely used by this and other authors, similar to other triamcinalone doses used for intramuscular depot injections. It is this author’s preference to avoid 40mg/cc concentrations because, after repeated injections, visible deposition of the triamcinalone suspension as white crystalline concretions can often be seen in the skin. These concretions must be manually removed with an 11-blade and fine-toothed forceps.
Pulsed dye laser (PDL) is a well-documented approach to keloid and hypertrophic scar therapy. It is best considered an adjunct to intralesional triamcinalone for treating particularly red vascular keloids and hypertrophic scars. PDL targets the oxyhemoglobin absorption peaks at 585-595nm within the red blood cells that travel throughout the tortuous minute blood vessels; thus, indirectly heating the intervening tissue. Although not completely understood, PDL is thought to soften the keloidal scar tissue by modulation of the fibroblasts and collagen itself.
Pressure dressings and pressure earrings are best used for earlobe keloids and can either be custom made, or ordered online, and should be used nearly continuously. Custom-made pressure dressings and braces may be difficult to find and are not routinely used.
Topical corticosteroids are adjunctive treatments and are minimally effective, as they do not penetrate the bulk of the scar tissue. In general, topical steroids should be avoided, as they will likely only create epidermal atrophy and potentially worsen the cosmetic appearance of the keloid.
Recently, some investigators have shown imiquimod to be effective at preventing keloid recurrence after tangential shave excision. It is proposed that imiquimod may help modulate the wound environment during granulation and inhibit regrowth of keloidal tissue. The efficacy of this technique has been debated, as only marginal success has been reproduced when compared to shave excision alone. Additionally, healing times are prolonged with imiquimod application, and the patient dropout rate is high. This technique should be considered an experimental modality.
Cryotherapy has seen a resurgence as an alternative, and possibly first-line treatment, for refractory keloids. A series of cryotherapy treatments is needed, and ulceration is frequently seen. Risks of hypopigmentation are real and patients should be carefully selected for this approach.
More advanced management with intralesional interferon alpha or verapamil, or topical mitomycin C, are outside the scope of this forum, but protocols are available in the literature.
In refractory or debilitating cases, referral to radiation oncology for consideration for radiotherapy is quite helpful, particularly in large broad keloids and in difficult cases of acne keloidalis nuchae.
After reaching a clinical endpoint of maximal improvement, either close observation or preparation for excision of selected small lesions should be the next step.
On the horizon, future therapy with injectable biologic agents, such as bacterial-derived collagenases, might provide another option for debilitating keloids. FDA-approved products, such as Xiaflextm (collagenase clostridium histolyticum) have been developed for use in Dupuytren’s contracture. One disappointing study from 2006 that investigated similar collagenases demonstrated a short-term and partial decrease in keloid scar volume, lasting less than 6 months, and no detectable effect on hypertrophic scars. A significant number of moderate complications were reported.
As stated above, topical therapies should be started early in treatment, but the expectations should be kept modest. It is often stated that topical home therapy (e.g. silicone sheeting) will slow down or halt the progression of a keloid, and in some instances, may decrease the size and symptoms of a keloid. Rarely does topical therapy completely resolve the keloid. It should be used to empower the patient to be involved in his or her care, and to maintain clinical improvements between office-based treatment sessions.
The patient should understand that the treatment of keloids and hypertrophic scars is a long-term commitment. Periodic ILT injections, and possible combination with PDL, should be the bulk of the approach. The injections or PDL should be started at monthly or at 8-week intervals as soon as keloid formation is suspected. Some advocate starting ILT at the time of suture removal in known keloid or hypertrophic scar-formers.
It should be further explained that ILT will soften the scar, and PDL may help fade the vascular blush of the scar, but neither modality will likely make the lesion vanish.
If the keloid appears clinically red in nature, then PDL should be advocated as an adjunctive therapy. Photographs will also help preauthorize PDL with the patient’s insurance company, to assist with coverage for a series of treatments (CPT 17106-08).
Emphasis on flattening and minimizing scar appearance, rather than complete cosmetic eradication, is the goal.
Unusual Clinical Scenarios to Consider in Patient Management
Despite utilizing many different approaches to treat a keloid or hypertrophic scar, treatment failure is common. In these situations, referring the patient to another specialist, such as a plastic surgeon, may be necessary. It is important to work up the therapeutic ladder and consider alternative treatments, such as radiation therapy, when traditional modalities fail.
Similarly, complications such as atrophy with ILT injections or post-inflammatory hyperpigmentation with PDL are common. Careful selection of patients and techniques may minimize these complications.
In the setting of atrophy from ILT, a series of intradermal and subcutaneous saline injections (3-6 total at monthly intervals) has been suggested to reverse a portion of this atrophy. It is thought that the saline may wash out any residual steroid from the area of atrophy and act as a method of subcision, undermining the defect to promote dermal collagen deposition and minimize the atrophy.
What is the Evidence?
Fujiwara, M, Muragaki, Y, Ooshima, A. “Keloid-derived fibroblasts show increased secretion of factors involved in collagen turnover and depend on matrix metalloproteinases for migration”. Br J Dermatol. vol. 153. 2005. pp. 295-300. (This article elucidates the underlying cellular mechanics behind keloid growth and migration)
Fujiwara, M, Muragaki, Y, Ooshima, A. “Upregulation of transforming growth factor-beta1 and vascular endothelial growth factor in cultured keloid fibroblasts: relevance to angiogenic activity”. Arch Dermatol Res. vol. 297. 2005. pp. 161-9. (Explains the role of vascular factors involved in keloid growth and gives a rationale to PDL efficacy in treating keloids and hypertrophic scars)
Elsaie, ML, Choudhary, S. “Lasers for scar: a review and evidence-based appraisal”. J Drug Dermatol. vol. 9. 2010. pp. 1355-62. (An excellent review that verifies PDL as the gold standard for laser therapy for keloids. Includes the use of ablative and non-ablative lasers for atrophic scars.)
Davison, SP, Dayan, JH, Clemens, MW. “Efficacy of intralesional 5-fluorouracil and triamcinalone in the treatment of keloids”. Aesthet Surg J. vol. 29. 2009. pp. 40-6. (Retrospective review of over 100 keloids, showing a 92% reduction in keloid size in when using the combination of 5-fluorouracil and ILT, versus 73% reduction in the ILT group alone)
Ogawa, R, Yoshitatsu, S, Yoshida, K. “Is radiation therapy for keloids acceptable? The risk of radiation-induced carcinogenesis”. Plast Reconstr Surg. vol. 124. 2009. pp. 1196-201. (An extensive literature search revealed five cases of radiation-induced tumor during keloid treatment. The overall risk is exceptionally low, yet the treatment is highly effective.)
Rusciani, L, Paradisi, A, Alfano, C. “Cryotherapy in the treatment of keloids”. J Drugs Dermatol. vol. 5. 2006. pp. 591-5. (1Lesions  were treated; 80% of the lesions reportedly responded “very well,” with a mean 80% volume reduction. No recurrences were noted in the follow-up periods [12-72 months].)
Kang, N, Sivakumar, B, Sanders, R. “Intra-lesional injections of collagenase are ineffective in the treatment of keloids and hypertropic scars”. J Plast Recontr Aesthet Surg. vol. 59. 2006. pp. 693-9. (Five keloid patients and two hypertropic scar patients were injected with serial rounds of collagenase. Results showed only partial regression in three of the five keloid patients' lesions, and a full (or greater) return in volume after 6 months.
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.