Management of KeloidsBy: Thad RileyAdvisor: Bill GrimesMarch 24, 2006

What is a Keloid?Non-cancerous fibrous proliferations that occur in the dermis after trauma or injury to the skin Keloids grow beyond the boundaries of the original wound site (vs. hypertrophic scar) Etiological factors that determine how a scar becomes a keloid remain unknown

Who and Why?Individuals with darker-pigmented skin or who freckle are more predisposed Seen largely in Africans, African-Americans, Hispanics, and Asians Can be a familial/genetic predispositionCan be due to immunological causes Bottom line No one knows!

How? (Pathophysiology)A result of an overactive inflammatory response and fibroblast proliferationA result of an abnormal collagen deposition in healing skin wounds Skin wound tension is a contributing factor in keloid formationIndividuals with an inflammatory or infectious element are at a predisposition for keloids

Ready for the Pictures?

Where?Anterior Chest

Where?Mandibular angle

Where?Shoulder

Where?Earlobes

Where?Upper Arms & Upper Back

Where?Posterior NeckLateral Neck

SoWhats the Problem?

The ProblemPROBLEM is with the TREATMENT OPTIONSThe pathophysiology of these scars is so poorly understood that it is basically unknownSurgery is the only approved treatmentA successful surgical protocol for removal of these types of scars is greatly lackingSurgical treatments available today only provide temporary relief Often grow back and do so in an aggressive manner

Possible SolutionsSurgical excision alonePost-surgical treatment agents:Mitomycin C solution The dietary compound quercetin Imiquimod 5% topical creamIntralesional corticosteroid injection Topical silicone gel sheets

How they workMitomycin C solution (MC)An anti-neoplastic agentHas anti-proliferative effects on fibroblasts, stopping keloid formationMC effectively blocks angiogenesis during the healing process of the wound, thus inhibiting keloid developmentMC is widely available and relatively cheap

How they workThe dietary compound quercetinmost common sources: apples, onions, red wine, and ginkgo biloba. has strong anticancer, antioxidant, antiviral, anti-inflammatory, and antimicrobial characteristics Inhibit keloid fibroblast proliferation, collagen production, and contraction of keloid derived fibroblasts

How they workImiquimod 5% topical creamInduces apoptosis in keloidal tissue Intralesional corticosteroid injectionInhibit fibroblast growth and break down collagen depositionpostoperative steroid injection is the most common form of keloid treatmentcorticosteroids commonly used include hydrocortisone and dexamethasone.

How they workTopical silicone gel sheetsImpermeable to water, reduces hemostasis and therefore, decreases the hyperemia and fibrosis often associated with keloidshave been used for more than twenty years to help reduce the size of scarringefficacy and safety of the silicone gel sheets is well established.

And the Winner isImiquimod 5% topical cream

Analysis13 keloids from 12 patients were surgically removed All keloids were present for at least 1 year and free of any treatment for the past 2 months A thin layer of imiquimod 5% cream was applied topically each night for 8 weeks4 week asessmentsAt 24 weeks, no keloids had recurredPilot study of the effect of postoperative imiquimod 5% cream on the recurrence rate of excised keloids (Berman and Kaufman, 2002 )

Analysis2 cases of irritation and superficial erosion were reported; resolved with cessation of the creamAt the 24 week assessment, RECURRENCE RATES of keloids treated with imiquimod 5% cream were LOWER than any previously reported in the literature

Pilot study of the effect of postoperative imiquimod 5% cream on the recurrence rate of excised keloids (Berman and Kaufman, 2002 )

AnalysisStudy did not control for the effects of vehicle application or other potential variablesFurther comparative studies with longer follow-up periods are neededAdditional studies needed to determine dosing frequency and duration Pilot study of the effect of postoperative imiquimod 5% cream on the recurrence rate of excised keloids (Berman and Kaufman, 2002 )

ConclusionTo develop a successful treatment plan for the keloid, two things have to be done:1. Further research to better understand the causes behind keloid formation 2. Establish a standard surgical protocolIn short, the topic of keloids is greatly under-exposed.

One More

ReferencesBerman B, Kaufman J. Pilot study of the effect of postoperative imiquimod 5% cream on the recurrence rate of excised keloids. J Am Acad Dermatol. 2002; 47: S209-11.Berman B, Villa A. Imiquimod 5% cream for keloid management. Dermatol Surg. 2003; 29: 1050-51.Fortunato NH, Berry EC, Kohn ML. Berry and Kohns Operating Room Technique. 10th ed. St. Louis: Mosby-Year Book, Inc; 2003.Gold MH, Foster TD, Adair MA, Burlison K, Lewis T. Prevention of hypertrophic scars and keloids by the prophylactic use of topical silicone gel sheets following a surgical procedure in an office setting. Dermatol Surg. 2001; 27: 641-44.Hom DB. Treating the elusive keloid. Arch Otolaryngol Head Neck Surg. 2001; 127(9): 1140-43.Jacob SE, Berman B, Nassiri M, Vincek V. Topical application of imiquimod 5% cream to keloids alters expression genes associated with apoptosis. Brit J Dermatol. 2003; 149(66): 62-5.Kumar V, Abbas AK, Fausto N. Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elseiver Saunders, Inc; 2005.Phana TT, Lim IJ, Chan SY, Tan EK, Lee ST, Longaker MT. Suppression of transforming growth factor beta/smad signaling in keloid-derived fibroblasts by quercetin: implications for the treatment of excessive scars. J Trauma. 2004; 57(5): 1032-37.Phanb TT, See P, Tran E, Nguyen TTT, Chan SY, Lee ST, Huynh H. Suppression of insulin-like growth factor signaling pathway and collagen expression in keloid-derived fibroblasts by quercetin: its therapeutic potential use in the treatment and/or prevention of keloids. Brit J Dermatol. 2003; 148: 544-52.Talmi YP, Orenstein A, Wolf M, Kronenberg J. Use of mitomycin C for treatment of keloid: a preliminary report. Otolaryngol Head Neck Surg. 2005; 132: 598-601.Way LW, Doherty GM. Current surgical diagnosis and treatment. 11th ed. New York: McGraw-Hill; 2003.

Classified as either scars or benign tumors, keloids are non-cancerous fibrous proliferations that occur in the dermis after trauma or injury to the skin. Extending beyond the borders of the original wound, keloids are elevated. Often, the keloid scar is not proportional to the severity of the injury/ wound. In other words, the scar is often much larger than the seriousness of the wound.

Keloids are often confused with their pathological cousin, the hypertrophic scar. However, keloids differ from the hypertrophic scar as they grow beyond the boundaries of the original wound site

Unfortunately, the etiological factors that determine how a scar becomes a keloid remain unknown Although keloids can form in all races, individuals with darker-pigmented skin or who freckle are at a greater disposition. These benign tumors are seen largely in Africans, African-Americans, Hispanics, and Asians.

Since the exact cause and mechanism of the keloid is unknown, the reasons why these four races are more prone to keloids are also unidentified.

While at times keloids can be unprompted, there can be a familial/genetic predisposition to whether one will develop this type of scar, especially in the four previously mentioned races.

Immunological causes also play a role in those individuals that develop keloids. AGAIN, the understanding of why the keloids ever form remains a mystery. While the pathophysiology of the keloid is unknown, some theories have been proposed as to why these types of scars do form.

Theory 1 proposes that keloids form as a result of an overactive inflammatory response and fibroblast proliferation throughout the wound healing process. This reaction is a genetically inherited trait.

Theory 2 states that keloid formation is the result of an abnormal collagen deposition in skin wounds that are healing. Since they grow past the normal boundaries of the wound, keloids can become very large over an extended period of time.

Another contributing factor in keloid formation is skin wound tension. The most common areas or areas of greatest susceptibility include the anterior chest, upper arms, mandibular angle, shoulders, upper back, earlobes, and posterior and lateral neck. There are pictures of keloids at these common sites in the upcoming slides.

Individuals that have a cutaneous disorder with an inflammatory or infectious element (cellulitis, for example), tend to be at a predisposition for keloidsThe PROBLEM is with the TREATMENT OPTIONS.

The pathophysiology of these scars is so poorly understood that it is basically unknown. Successful treatment depends upon the further exploration and identification of the mechanisms that lead to the development of the keloid scars.

Currently, surgery is the only approved treatment to remove the keloid and consequently

A successful surgical protocol for removal of these types of scars is lacking, thus providing NO starting place for providers to begin treatment. Regrettably, the surgical treatments that are performed today only provide temporary relief because these scars often grow back and do so in an aggressive manner.

One such surgical treatment used is called simple surgical excision.The primary treatment of simple surgical excision has proven to be one of the LEAST effective methods in preventing the recurrence of keloids. More importantly, there is no surgical procedure or protocol that has been established to assist any medical provider in the successful removal of a keloid. The treatment of simple surgical excision is the surgical removal of keloids without the use of an additional injection, cream, steroid, or other drug that would help the wound heal without forming a keloid. As a result, simple surgical excision of keloids can lead to a recurrence rate of 50% to 80%. It was once thought good practice to leave a rim of the keloid tissue around the edges of the wound to reduce the likelihood of increased irritation of the surrounding tissue and therefore, lower the chance of keloid reformation. However, this technique lacks research and therefore, is not a proven one. It has been suggested that after surgical excision, monofilament sutures are ideal compared to braided types. The monofilament sutures are believed to help reduce microabscess formation and inflammation along the suture site. It is also important to minimize skin tension by avoiding Z-plasties and W-plasties, unless the scar goes across a concave or flexed area.Unfortunately, there is not an approved topical cream or injection to be administered to dissolve the keloid WITHOUT surgery. The most common method of treatment for this type of scar formation is to surgically excise it and then use an agent to help combat the keloid reformation. Post-surgical treatment agents include: Mitomycin C solution, The dietary compound quercetin, Imiquimod 5% topical cream, Intralesional corticosteroid injection, and Topical silicone gel sheets. The following three slides are a brief overview on each of the five treatment agents:

Mitomycin C is an anti-neoplastic agent. MC has anti-proliferative effects on fibroblasts, thus stopping keloid formation.

MC effectively blocks angiogenesis during the healing process of the wound, thus inhibiting keloid development

MC is widely available and relatively cheap

Quercetin, the most common flavonoid glycone, is found mostly in ones diet. The most common sources of quercetin include apples, onions, and red wine; it is also found in ginkgo biloba.

The dietary compound quercetin has strong anticancer, antioxidant, antiviral, anti-inflammatory, and antimicrobial characteristics.

Quercetin also inhibits keloid fibroblast proliferation, collagen production, and contraction of keloid derived fibroblasts.

Imiquimod 5% topical cream induces apoptosis in keloidal tissue. Intralesional corticosteroids inhibit fibroblast growth and break down collagen deposition.

The postoperative steroid injection is the most common form of keloid treatment

The corticosteroids commonly used for injections include hydrocortisone and dexamethasone. Topical silicone gel sheets are impermeable to water, reduce hemostasis and therefore, decrease the hyperemia and fibrosis often associated with keloids.This process leads to the flattening of the raised keloid scar. It is through the increased hydration and occlusion of the wound by which the silicone gel sheets work.

The silicone gel sheets have been used for more than twenty years to help reduce the size of scarring. Fortunately, the efficacy and safety of the silicone gel sheets is well established.

While one of the previously five agents has not been proven more effective over another, each can be used as an adjunct therapy in treatment for the keloid.

All of the previously mention agents prove to be successful in their own ways. If asked to pick one treatment over another, analysis of the research could lead one to choose

the imiquimod 5% cream. The cream is easily available and very inexpensive while proving to be extremely efficient in preventing keloid reformation. Now we will look at a study that supports this claim.The study titled, Pilot study of the effect of postoperative imiquimod 5% cream on the recurrence rate of excised keloids, looks at the effects of imiquimod 5% cream used postoperatively. Thirteen keloids from twelve patients were surgically removed.

In the patients selected for the study, all keloids were present for at least one year and free of any treatment for the past two months.

A thin layer of imiquimod 5% cream was applied topically each night for eight weeks, starting with the night of surgery.

Patients were assessed every four weeks for any erosions, edema, pigment alteration, erythema, and/or recurrence of keloids.

At twenty-four weeks, no keloids had recurred. Two cases of irritation and superficial erosion were reported, but were resolved with cessation of the imiquimod 5% cream. However, both patients sill completed eight weeks of imiquimod 5% cream therapy and the final assessment at twenty-four weeks. Participants could not be pregnant, nursing, have severe preexisting heart disease, uncontrolled hypertension, or an autoimmune disease. Furthermore, all patients were above the age 18 and consented to participation and surgery.

At the twenty-four-week assessment, recurrence rates of keloids treated with imiquimod 5% cream were lower than any previously reported in the literature. Unfortunately, the study did not control for the effects of vehicle application or other potential variables.

Thus, further comparative studies with longer follow-up periods are necessary.

Additional studies are needed to determine dosing frequency and duration.

To develop a successful treatment plan for the mysterious keloid, two things have to happen.

First, further research must be done to better understand the causes behind the keloid formation as well as why certain races are more at risk than others. Regrettably, there is just so little that is known about the keloid.

Second, a standard surgical protocol must be established to provide all medical practitioners with the same foundation and basis in treatment. The need for this can not be stressed enough for the establishment of such would provide all practitioners with the same foundation, the same starting point from which to begin treatment. By establishing a surgical protocol for removal of the keloid, a commonality in the treatment process for this elusive scar would be created and thus, half of the battle would already be over.

In short, the topic of keloids is one that is greatly under-exposed!