German S2k guidelines for the therapy of pathological ... · 10/3/2012 · For keloids the genetic...

DOI: 10.1111/j.1610-0387.2012.08012.x Guidelines 1

© Deutsche Dermatologische Gesellschaft • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2012 JDDG | 2012 (Band 10)

PreambleThe present guideline was primarily pre-pared by representatives of the field der-matology and dermatosurgery and is ba-sed on the S1 guideline of the GermanSociety of Dermatology from 2004 [1]. Besides the dermatologists many otherdisciplines are involved in the treat-ment of keloids. The German Societyof Plastic, Reconstructive and AestheticSurgeons participated in the reviewprocess of this guideline and funda-mentally agrees with the content. Forfurther update inclusion of all relevantmedical societies already in the initialstage as well as an even more detaileddepiction of surgical therapy optionsare planned.

List of abbreviations used5-FU, 5-fluorouracil; CI, confidence in-terval; cw-CO2 laser, continuous-waveCO2 laser; Er:YAG laser, er-bium:yttrium-aluminum-garnet laser;FPDL, flashlamp-pumped pulsed dye la-ser; Gy, gray; HTS, hypertrophic scar; IF,interferon; NaCl, sodium chloride; RR,relative risk; TGF, transforming growthfactor; TAC, triamcinolone acetonide

1 Aims/addressees 1.1 Target groupThis guideline is targeted at dermatolo-gists in office practice and clinics, whoare involved in the treatment of hyper-trophic scars and keloids.

1.2 Aims of the guideline1. Stage-adapted and symptom-oriented

selection of therapies to optimizetherapy success

2. Avoidance of performing insufficienttherapies or of therapies without ade-quate dosage and corresponding lackof anticipated therapy success

3. Reduction of insecurity in perfor-ming rarer therapy forms

1.3 Participating medical societiesGerman Society of Dermatology(DDG) represented by: Prof. Dr. SabineEming, Cologne; Dr. Gerd Gauglitz,Munich; Dr. Silvia Hohenleutner, Re-gensburg; Prof. Dr. Günther Sebastian,DresdenProfessional Association of German Dermatologists (BVDD) and EuropeanSociety of Laser Dermatology (ESLD)represented by: Dr. Klaus Fritz, Landau

Austrian Society of Dermatology and Venereology (ÖGDV) and Austrian Society for Dermatosurgery (ÖGDC)represented by: Dr. Josef Koller, SalzburgGerman Society for Dermatosurgery(DGDC) and German Society for Der-mopharmacy (GD) represented by: PDDr. Joachim Fluhr, BerlinSwiss Society of Dermatology and Vene-reology (SGDV) represented by: Prof.Dr. Renato Panizzon, LausanneParticipation in the review process: Ger-man Society of Plastic, Reconstructiveand Aesthetic SurgeonsProject management/methodic coordi-nation: PD Dr. Alexander Nast, Dr.Birte Sporbeck, Division of Evidence-Based Medicine (dEBM), Charité – University Medicine Berlin, Berlin

2 Methods This guideline is based on the update ofthe DDG guideline “Keloids and hyper-trophic scars” (S1 guideline) developedin 2004 [1]. The guideline was developed accordingto the methodic stipulations on deve-lopment and further development ofguidelines for diagnostics and therapy

Guideline

German S2k guidelines for the therapy of pathologicalscars (hypertrophic scars and keloids)Alexander Nast1, Sabine Eming2, Joachim Fluhr3, Klaus Fritz4, Gerd Gauglitz5, Silvia Hohenleutner6, Renato G. Panizzon7, Günther Sebastian8, Birte Sporbeck1, Josef Koller9

(1) Division of Evidence-Based Medicine (dEBM), Department of Dermatology, Charité – Universitätsmedizin Berlin,Germany

(2) Department of Dermatology and Venereology, University of Cologne, Germany(3) Department of Dermatology, Charité – Universitätsmedizin Berlin, Germany (4) Dermatologists and Laser Center Landau and Kandel, Landau (Lower Palatinate)/Kandel, Germany; Department of

Dermatology, Inselspital Bern, Switzerland; Department of Dermatology, Environmental Medicine and HealthTheory, University of Osnabrück, Germany

(5) Department of Dermatology and Allergology, Ludwig Maximilian University of Munich, Germany (6) Department of Dermatology, University of Regensburg, Germany(7) University Clinic for Dermatology, Lausanne, Switzerland(8) Dermatologist, Dresden, Germany(9) University Clinic for Dermatology, Salzburg State Hospital, University Clinic of the PMU, Salzburg, Austria

Section EditorPD Dr. Alexander Nast,

Berlin

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JDDG | 2012 (Band 10) © Deutsche Dermatologische Gesellschaft • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2012

of the Association of the Scientific Me-dical Societies in Germany (AWMF)and in the three-level concept of theAWMF corresponds to an S2k guide-line [2]. The therapy options considered and eva-luated are a selection of the guidelinesgroup and in their view represent parti-cularly relevant treatment possibilities.Besides the evaluated therapies furtheroptions are available; their evaluation isnot subject of the guideline.All recommendations were approved in aconsensus conference employing a for-mal consensus process (nominal groupprocess). First the state of evidence waspresented from the expert viewpointwith subsequent discussion. Each groupmember made comments on the draft re-commendations; divergent proposalswere noted. The steps serial discussion,preliminary vote, debate/discussion aswell as the final vote followed. In all vo-tes strong consensus (>90 %) could beachieved. The consensus conference tookplace in Berlin on 7 Nov. 2011. Forthose interventions for which due totime constraints no consensus was achie-ved at the consensus conference an on-line consensus conference was conductedwith the same method as in the live con-ference. If desired, the results of the votecan be obtained from the guidelinesgroup. The moderation of the consensusconference was conducted by Dr. Alex-ander Nast, who is an AWMF guidelinesadvisor. All representatives nominated bythe medical societies were qualified tovote. For standardization uniform formulati-ons were employed for the recommenda-tions of the guideline. The following levels are valid:

All consensus passages are highlighted inthe text with a grey box.

Strongrecommendation

Is recommended

Weak recommendation

Can berecommended

Open recommendation

Can be considered

Recommendationagainst an inter-vention

Is not recommended

Absolute recom-mendation againstan intervention

Should not beused

3 Biological aspects of woundhealing and scar formation

Sabine EmingPhysiological wound healing of the skinis a complex and cascade-like processbiologically with the goal of restoring theintegrity of the damaged tissue [3]. Initi-ally there is a marked inflammatory reac-tion to eliminate defective tissue and pa-thogens. The formation of new bloodvessels, the activation of keratinocytesand fibroblasts at the edge of the woundas well as the synthesis of extracellularmatrix components follow. After woundclosure through epithelialization the der-mal granulation tissue is restructuredinto a scar and the replacement tissue ad-apts to biomechanical requirements. Inthis process the differentiation of fibrob-lasts into myofibroblasts that are particu-larly stimulated by transforming growthfactor-�1 (TGF-�1) plays a central role.Myofibroblasts are characterized by con-tractile actin filaments and a high pro-duction of collagen and take on an im-portant function in the contraction andreorganization of the granulation tissue.It is assumed today, that the decrease ofmyofibroblasts in wound tissue after wo-und closure is of great significance in li-miting scar formation [4]. The dynamics of wound healing is coor-dinated through a controlled interactionof numerous soluble factors, compo-nents of the extracellular matrix and dif-ferent cells. Scar tissue differs from unda-maged skin by the loss of skinappendages, flattening of the rete ridges,altered architecture and composition ofthe extracellular matrix components andfinally by limited mechanical properties.A regeneration of damaged tissue (resti-tutio ad integrum) is possible only in fe-tal skin [5]. Even though great advancesin the understanding of molecular me-chanism of the healing process have beenmade in the past decades, it still remainsunclear why no postnatal regenerationtakes place in humans, but that to a vary-ing extent scars always are formed.

3.1 Definition of keloid and hypertrophic scar

Sabine EmingKeloids and HTS are benign, localizedproliferations of connective tissue of theskin and a result of a disturbed interac-tion of cytokines, cells and the surroun-ding extracellular matrix involved in thehealing process. Keloids and HTS can be

differentiated clinically and histologi-cally; their characteristics are contrastedin Table 1 (Table 1). Even though theimpact of numerous endogenous andexogenous factors on the extent of scartissue has been well-illustrated, the mole-cular basis of pathological scar formationis still poorly understood to date. Patho-logical scar formation is a reflection ofdisturbed wound healing with a prolon-ged and disturbed inflammatory phaseand the resulting increased formationand reduced degradation of the extracel-lular matrix. Experiments on cells isola-ted from keloid tissue demonstrate nu-merous alterations on their functionsuch as e.g. in proliferation, apoptosisand/or expression of growth factors andmatrix molecules [6]. These observationsin part are the basis for the developmentof new therapy approaches. It is assumedthat the disturbed reduction of the myo-fibroblasts and their prolonged activa-tion in granulation tissue lead to an im-balance in favor of connective tissuesynthesis. The effect of mechanical forceson the wound fibroblasts/myofibroblastsis of particular significance and possiblycontributes to increased connective tis-sue synthesis via autocrine stimulation of the cells [4, 7, 8]. This in part explainsthe effectiveness of operations that relieve tissue tension in the vicinity ofthe scar. Possibly an altered concentra-tion relationship of different TGF-�isoforms in the activation of the fibrob-lasts/myofibroblasts also plays a centralrole [9]. Due to familial tendency to develop keloids, for several years severalgenetic factors have been discussed (e.g.genes regulating apoptosis, mitogen-activated protein kinase, TGF-� signalcascade, interleukin-6, plasminogen ac-tivator inhibitor-1) [10]. Of particular relevance for therapy is the fact that HTS occur without geneticpredisposition and can regress sponta-neously or through therapy. For keloidsthe genetic predisposition must be kept inmind and that, for example, after surgical measures or injuries to the skinrecurrences must always be expected [11].

4 General recommendations on the treatment of keloids and hypertrophic scars

Alexander Nast4.1 Necessity of treatmentIn principle HTS and keloids are benignskin lesions. The need for treatment

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results from symptoms (e.g. itch/pain),from functional impairment (e.g. con-traction/mechanical irritation due to elevation) as well as on aesthetic/cosmeticgrounds, that can greatly impact qualityof life and cause stigmatization [12].Bock et al. developed an instrument to assess quality of life specifically for patients with HTS and keloids. In thevalidation study a severe impairment ofquality of life was also observed [13].

4.2 Therapy goals/quality indicatorsThe therapy goals must be set on an in-dividual basis and be oriented to thecomplaints of the patient. Depending onthe treatment option marked improve-ment should be achieved after 3–6 treat-ments or after 3–6 months (e.g. volumereduction by 30–50 %, symptom reduc-tion > 50 % and/or sufficient satisfactionof the patient).

With none of the methods of scartherapy available at present will it suc-ceed in all cases to achieve scar reductionor an improvement of the functionaland/or cosmetic situation. The treat-ment method of first choice cannot bestandardized for scars, as too many varia-bles in the development and regression

In case of a lack of satisfactory treat-ment success after 3–6 treatments/ 3–6 months a modification of the tre-atment strategy (combination/switch/dose increase) is recommended.

of scars (e.g. location, age and type ofscar, genetic disposition etc.) impact theprocess. Often a combination of diffe-rent treatment methods is required.

4.3 Classification and evaluation of therapy success

For the clinical routine particularly docu-mentation of size and thickness as well asphoto documentation are practical. Furt-her, the satisfaction of the patient and re-duction of symptoms are of relevance. For clinical studies at present particularlythe Vancouver Scar Scale (VSS), PatientScar Assessment Scale (POSAS), VisualAnalog Scale (VAS), two-dimensionalkeloid modeling as well as mid- to high-resolution B-image sonography are em-ployed. Nonetheless, the subjective asses-sment scales are of only limitedsuitability for large scars or to evaluatefunctional impact [14–16].

4.4 Therapy algorithmsThe therapy algorithms for the treat-ment of HTS and keloids are depicted in Figure 1, Figure 2 and Figure 3 (Figure 1–3).

4.5 Exemplary casesHypertrophic scarBackground information: A 34-year-oldwoman, involved in a car accident aboutthree years ago, developed HTS, pruritusand moderate pain. Scars elevated by ab-out 2–3 cm. Patient with a great desirefor treatment (Figure 4).

Therapy: Injection of triamcinolone ace-tonide (TAC) or cryotherapy, in case ofpersistent redness, use of flashlamp-pumped pulsed dye laser (FPDL) every4–6 weeks orcompression and conservative topicaltherapy, in case of persistent redness useof FPDL every 4–6 weeksorwith a history of delayed epithelializa-tion (after the accident and deep ulcera-tion) in individual cases: excision andsubsequent conservative topical therapyif indicated.

Aesthetically unacceptablehypertrophic scarBackground information: Cord-like HTSin the face after prolonged healing of atraumatic deep abrasion. The patienthad no history of a tendency to developHTS or keloids (Figure 5). Therapy: Complete (extra-marginal) ex-cision with plastic reconstruction withintracutaneous suture. Aftercare withconservative topical therapy if indicated.

Small keloidBackground information: Spontaneouskeloid in a 40-year-old woman, existencesince about one year, pruritus and thedesire for treatment (Figure 6).Therapy: Strictly intralesional injectionof TAC and/or cryotherapy, in the eventof persistent redness use of FPDL every4–6 weeks, start with about 5–6 J/cm2.

Table 1: Hypertrophic scar and keloid: clinical and histological characteristics.

Characteristics Hypertrophic scar Keloid

Incidence Frequent Rare, increases with increasing skin pigmentation

Extent Limited to the original injury Goes beyond injury

Occurrence <6 months after injury >6 months after injury

Regression Frequent None

Previous injury YesYes, but often “minimal trauma” unnoticed by thepatient (e.g. folliculitis, scratch or insect bite)

Location Entire skin surface Entire skin surface, often ear lobe, sternum, nape

Genetic predisposition Not known Yes

Histology

- �-actin positive myofibroblasts- Collagen fibers in wave-like

patterns arranged parallel to theepidermis

- Reduced apoptosis- Increased blood vessel development- Thick collagen fibers, in part parallel to the

epidermis, in part nodular arranged- Cell-poor center

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Mid-sized keloidBackground information: Excision of be-nign skin tumor two years ago, in thefurther course development of a keloid.Moderate pruritus (Figure 7). Therapy: Strictly intralesional injectionof TAC in combination with cryo-therapy.

Small-based keloid Background information: A 33-year-oldwomen, ear piercing about 15 years ago, development of a keloid, surgery 10 years ago without aftercare resultingin a recurrence (Figure 8). Therapy: Surgical removal/CO2 laser ab-lation, after-treatment with TAC and/orcryotherapy (day 0, depending on fin-dings then about every 4 weeks) and

pressure treatment and/or silicone if indicated.

Functionally limiting hypertrophicscars/keloidsBackground information: Extensive HTSon the foot with transition into a keloidfollowing a grade IIb burn treated con-servatively. This is a 10-year-old boy withrapid growth leading to a contracture ofthe second to fourth toe with the imme-diate need for action (Figure 9). Therapy: Prompt complete excision of thescar with elimination of the scar’s pull onthe toes. Closure of the defect with a full-thickness graft from the groin region andin part with a split-thickness graft fromthe scar itself. Subsequently compressionand conservative topical therapy.

5 Evaluation of the individualtherapy options

5.1 CorticosteroidsGerd GauglitzMechanism of action Corticosteroids reduce the excessive gro-wth of the scar by diminishing collagensynthesis as well as glycosaminoglycansynthesis and inhibiting fibroblast proli-feration. In addition to the well-knownantiinflammatory effect of corticostero-ids there is an inhibition of iNOS tran-scription (iNOS, inducible form of NOsynthase [17]) with reduction of collagenproduction in fibroblasts and inhibitionof alpha2-macroglobulin synthesis, aninhibitor of collagenase.

Side effectsThe injections are painful. With toodeep injection, atrophy of the subcutismay develop; with too superficial injec-tion, telangiectases and disturbed pig-mentation can occur. White deposits ofthe crystal suspension can develop.

Response rate/recurrence rateThe response rate in keloids is about 50–100 %. The recurrence rate is reported tobe about 9–50 % [18].

PerformanceMost often TAC, 10–40 mg, maximally5 mg/cm2, pure or diluted with 0.9 %NaCl or lidocaine 1:2 to 1:4 is injected.The injection is performed with a Luer-Lok syringe strictly intralesionally. Ablanching effect signals the endpoint ofthe infiltration. Further injections areperformed as needed at 3-4-week inter-vals. One study demonstrated that bystarting with a low TAC concentration(10 mg/ml) with an increase during thecourse (20 or 40 mg/ml) the risk of sideeffects as well as the recurrence rate canbe decreased [19]. The performance ofsuperficial cryotherapy immediately be-fore intralesional corticosteroid injectionfacilitates the subsequent corticosteroidinjection through the development ofedema [20]. In freshly operated scarsTAC treatment can obviously be perfor-med on the day of surgery without disad-vantage [21].

OtherAs explained by their mechanism of ac-tion, corticosteroids are most effectivefor active lesions, such as erythematous,pruritic or painful scars.

Figure 1: Therapy algorithm hypertrophic scar.

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Figure 2: Therapy algorithm keloid (part I).

Figure 3: Therapy algorithm keloid (part II).

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5.2 CryotherapyGerd GauglitzMechanism of action The effects are based especially on chan-ges in microcirculation with cold-indu-ced alteration, thrombosis and consecu-tive ischemic cell death.

Side effectsProtracted healing time of about fourweeks and frequent (reversible) depig-mentation due to destruction of thecold-sensitive melanocytes.

Recommendation corticosteroidsTherapy of HTS and keloids withstrictly intralesional injection of corti-costeroids is recommended. In HTS and keloids a combinationwith cryotherapy is recommended. Purely topical use in the form of creamsor ointments is not recommended. The use of corticosteroid injections after surgical therapy of keloids is re-commended. The use of corticosteroid injectionspostoperatively for prevention of denovo development of HTS or keloidsin patients at risk/with a predispositioncan be considered.

Response rate/recurrence rateZouboulis et al. report of “excellent res-ponse” or “good response” in 62.5 % ofpatients with keloids and HTS, with

HTS responding more rapidly thankeloids (in 53 % of HTS patients <3 treatments being required, in 16 % ofkeloid patients <3 treatments necessary)

Figure 4: Hypertrophic scar.

Figure 5: Aesthetic unacceptable hypertrophic scar before and after surgical therapy.

Figure 6: Small keloid before and after therapy.

Figure 7: Mid-sized keloid.

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[22]. Ernst et al. [23] report a responserate of 82 % in HTS and 64 % inkeloids.

PerformanceFundamentally, different approaches canbe distinguished:1. Short cryotherapy especially in com-

bination with TAC to facilitate theinjection of TAC.

2. Intensive cryotherapy with completefreezing of the tissue.

Spray and contact as well as intralesionalcryotherapy can be performed. Repetition of the procedure in 4–6-weekintervals until the lesion is completelyflattened is usually necessary.

OtherThe patient should be warned to expect ablister progressing to a weeping wound

and treated with antiseptics if indicated.The next treatment should take placeonly after healing of the defect caused bythe previous treatment.

Recommendation cryotherapyTherapy of HTS (small) as well askeloids with cryotherapy is recommen-ded. Therapy of keloids with cryotherapy incombination with triamcinolone is re-commended. The use of cryotherapy after surgicaltherapy of keloids can be recommen-ded in individual cases. The use of cryotherapy postoperativelyas prophylaxis of de novo developmentof HTS or keloids in patients at risk/with a predisposition is not recom-mended.

5.3 Pressure therapyJoachim FluhrMechanism of actionTopical pressure reduces capillary perfu-sion, accelerates maturation of collagenand thereby flattening of the scar.

Side effectsUnpleasant sensations due to heat, swea-ting and swelling of the limbs, dermati-tis, pressure erosions and ulcerations.

Response rate/recurrence rateNo clear positive effect of compressiongarments was found in a meta-analysis[24]. By use of specific pressure instru-ments (e.g. magnetic buttons, stents, oy-ster-shell sculptures) good response ratesparticularly on the ear have been repor-ted [25, 26]. The use of 20–25 mmHgwas significantly superior to treatment ofHTS with 10–15 mmHg [27]. A defi-nite statement on the recurrence ratecannot be made, as the follow-up periodin most studies was only several months.

Performance Pressure therapy usually using elastic materials should be started as early as pos-sible (i.e. with conclusion of re-epithelia-lization), when a tendency for develop-ment of pathological scars is known evenpreventively. The required pressure is 20–30 mmHg (corresponds to compressionclass II) and should be continued thewhole day, i.e. 24 hours. Pressure therapyis usually performed with pressure suitsor bandages, sometimes with transparentplastic masks or pressure buttons in spe-cial locations. With compression banda-ges made out of the to be favored longstretch material, slight differences in cir-cumference (e.g. edema) has less of animpact than with short stretch material,so that the still tolerable maximum pres-sure is reached distinctly later, while onthe other hand the still effective mini-mum pressure is less likely to be fallenshort of. In the individually made pres-sure bandages the applied pressure decli-nes after about six months due to the ma-terial. A slow reduction of the pressureover the course of the treatment period of6–24 months can be done. In postopera-tive prophylaxis the treatment periodshould last at least 6–24 months.

OtherThe therapy is time-consuming for the patient and places high demands on

Figure 8: Small-based keloid.

Figure 9: Large hypertrophic scar before and after combined therapy.

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patient and physician with respect to adherence. The therapy is in part associated withhigh costs, so that documentation of theinitial findings and course should parti-cularly be considered.

5.4 Surgical aspects of the treatmentof keloids and hypertrophic scars

Josef KollerMechanism of actionDepending on the individual initial si-tuation and pathogenesis of the scar for-mation three important mechanisms ofaction come in to be useful in surgicalwound treatment: 1. The increased tension represents a cen-

tral aspect in the development of aHTS. The successful removal of thescar tract can be achieved with Z- orW-plasty or by use of grafts or localskin flaps. All methods mentioned inthe end effect lengthen the scar and in-terrupt the vicious circle between scartension and consecutive further thicke-ning of the scar due to permanently sti-mulated collagen production.

2. HTS and keloids that developed onthe basis of delayed wound healing(e.g. deep dermal burn or wound in-fection) are transformed by surgery(excision with suture or graft) into awound with a short healing time.

3. Through the surgical removal of scartissue a situation corresponding to afresh wound still without fibrosis isachieved, in which renewed excessivescarring can be reduced by adjuvantconservative therapy.

Side effectsIn the event of wound infections, necro-sis of skin flaps and graft rejection de-layed wound healing can again result inthe development of a possibly even largerscar than preoperatively. In addition,particularly when a respective disposi-

Recommendation pressure therapy Therapy of HTS and keloids withpressure can especially be recommen-ded for extensive scars and keloids orin special locations (e.g. on the ear). Particularly when there is a known ten-dency to HTS and keloids postoperati-vely as well as after surgical removal ofpreexisting HTS and keloids pressuretreatment can be recommended in sui-table locations.

tion is present a recurrence occurs whensurgical after-treatment does not elimi-nate the most important pathogeneticfactors, namely the increased tension onthe scar.

Response rate/recurrence rateHardly any studies with sufficient me-thodic quality exist for surgery of scars[28]. Among others, this may be due tothe fact that in part HTS are not diffe-rentiated from keloids (which at timesmay be difficult) or follow-up times weretoo short. The recurrence rates followingsimple surgical excision therefore fluc-tuates between 45 to 100 % [29]. Keloidexcisions can be performed intra- or ex-tra-marginally. In a recent study on 75patients with intra- vs. extra-marginalexcision a significantly lower recurrencerate was seen in completely excisedkeloids in comparison to those not com-pletely removed at the edge or the wo-und base [30]. A modification of the in-tramarginal excision method has beenreported by Lee [32] and by Kim [32].The skin above the keloid is lifted as apedicled flap; subsequently the underly-ing scar tissue is excised. The previouslyformed skin flap is used for closure of thedefect. Lee reported that in the observa-tion period no recurrence was seen inany keloid that healed without complica-tions and was not treated in an adjuvantmanner. Kim et al. [32] observed a recur-rence in four of nine cases (all withoutadjuvant concomitant therapy). Most studies, nonetheless, evaluate com-bination techniques with surgical exci-sion and adjuvant radiotherapy, pressuretherapy, intralesional corticosteroids andsilicone dressings [33]. The combination of excision and posto-perative intralesional corticosteroid injec-tion (40 mg triamcinolone monthly overat least three months) resulted in no re-currence in twelve patients with earlobekeloids with a follow-up between threeand 16 months [34]. Using a similar regi-men Rosen et al. [35] observed a keloidrecurrence in 23 % of the patients.The combination of excision and pres-sure therapy with magnetic buttons inmore than 1,400 ear keloids resulted in arecurrence-free rate of almost 90 % with18 months of follow-up [36]; Hassel et al. [37] achieved a similar result withan “oyster splinter” technique.The combination of excision with subse-quent postoperative radiotherapy resul-

ted in freedom from recurrence in 84 %after five years with only slight differen-ces between the individual locations (ear-lobe, presternal, etc.) [38]. Nevertheless,van de Kar in a prospective study on pre-viously successfully surgically and/orconservatively treated patients a recur-rence rate of 72 % after extra-marginalexcision and postoperative radiationtherapy [39]. Excision and silicone gel dressings: Thestudies on this subject are contradictory.In a Cochrane Database Review the aut-hors conclude that only weak evidenceexists for an advantage of silicone gelfilms in the prevention of HTS andkeloids following excision [40]. Excision and imiquimod in keloids onthe trunk: After positive initial reportsCação et al. [41] and Malhotra [42] fo-und no efficacy of imiquimod 5 %cream in keloids on the trunk after sur-gical excision.

PerformanceFor surgical correction of uncomplicatedHTS there exists a fundamental recom-mendation to perform this at the earliestone year after the development of thescar due to the frequent spontaneous re-gression. Excluded from this are contrac-tures causing functional impairment(e.g. limited opening of the mouth, lif-ting the head, extending the fingers, etc.)or a disfiguring scar in a cosmetically im-portant location. The waiting period usually does not ap-ply to keloids, as surgery is usually per-formed only after the failure of conserva-tive treatment option. In keloids, surgeryis combined with adjuvant treatment; inHTS (particularly in recurrences) adju-vant treatment can be employed.

The surgical techniques for the two scartypes are in principle the same. Z- andW-plasty are, nonetheless, employed al-most exclusively for HTS. With excision and primary wound clo-sure, among others, small HTS that de-veloped on the basis of disturbed woundhealing with delayed healing as well assmall keloids can be treated [43]. Z- andW-plasty displace the tension on theHTS by up to 90 % and lengthen thescar. The resulting relief of tension canaffect a lack of recurrence.Split- and full-thickness skin grafts aresuited primarily for covering larger, ex-tensive scars that developed on the basis

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of a wound healing disturbance (e.g.deep dermal burn). Local flaps, distantflaps and the tissue expander are occasio-nally employed particularly for broadscar strands. Because of the underlying genetic predis-position, following surgical removal ofkeloids, a recurrence must be expected.

5.5 Ablative laser therapy Silvia HohenleutnerLaser devicesContinual-wave CO2 laser (cw-CO2 laser),pulsed erbium:yttrium-aluminum-garnetlaser (Er:YAG laser)

Mechanism of action Due to the high absorption of laser lightin water vaporization (CO2 laser) or ex-plosion-like ablation (Er:YAG laser) oftissue occurs. The aim of ablative lasertreatment in keloids or HTS is flatteningof the exophytic scar tissue.

Side effectsErosions, weeping, crusting and erythemaof longer persistence are obligatory in

Recommendation surgical therapySurgical therapy of HTS without ten-sion and without cosmetic disfigure-ment with an age of less than one yearis not recommended. HTS under tension should be relievedof the strain primarily surgically in atimely manner (Z- or W-plasty, graftsor flaps) particularly when contractu-res with functional limitations have al-ready developed. The excision of small, cosmeticallydistressing HTS that developed on thebasis of disturbed wound healing canbe recommended. For small-based larger keloids primarysurgical therapy can be recommended.For all other keloids surgical therapy isrecommended only after the failure ofconservative therapy.No final judgment can be made, if intra- or extra-marginal excision is tobe favored. The combination of surgical keloidtherapy with an after-therapy (e.g. intralesional corticosteroid, pressuretherapy, radiation, cryotherapy) is re-commended in principle. No final judgment can be made onwhich after-therapy achieves the bestresults.

ablative laser therapy. De- and hyperpig-mentation are more marked and persistlonger after CO2 laser therapy than afterthe Er:YAG laser which ablates almostwithout heat. Viral or bacterial superin-fections are further possible complications.

Response rateSome reviews suggest a recurrence ratefor HTS after CO2 laser treatment of upto 92% , often citing Apfelberg et al.[44]. In the cited study, however, onlykeloids were treated. A differentiationbetween proliferating keloids and HTSwith tendency for spontaneous regres-sion is of great importance in determi-ning the indication. No longer active, “burned out” HTS(e.g. burn scars with bridges or contrac-ture formation, incompletely regressedsurgical or trauma scars after a “wait-and-see strategy”, step formation afterinaccurate adaptation of surgical woundedges or after bites) can often be exactlyflattened by ablative laser techniques andin a bloodless manner in comparison toscalpel excision through the possibility ofablation in layers. In keloids, due to the above-mentionedtendency to recur, ablative laser therapyjust as excision as monotherapy is usuallycontraindicated. Particularly in large exo-phytic keloids, where therapy with othermethods alone does not appear promi-sing, a CO2 laser removal of the exophy-tic portion in the sense of debulking canbe attempted. To avoid a recurrence thismust definitely be combined with otherprocedures such as intralesional cortico-steroid injections, cryotherapy, pressuretherapy or radiation therapy. In broad-based ear keloids, for example, good re-sults can be achieved by ablation followedby compression therapy with speciallyconstructed ear clips [45].

PerformanceTissue removal in fine HTS, step or con-tracture formation can be performedathermically with little damage to surro-unding tissue with the Er:YAG laser. Inlarger scar volumes and hard scar tissuethe cw-CO2 laser is superior due to thebetter hemostasis and its greater efficacyin tissue removal. After CO2 laser removal of keloids corti-costeroid injections or cryotherapy maybe started immediately postoperativelyand be repeated at intervals of three tofour weeks over a longer period of time.

The patient should always be informedthat due to the genetic predispositionthat even with laser surgical removal ofkeloids a recurrence must be expected.

Other Due to a lack of controlled studies, nostatement can yet be made on the use of the fractional CO2 laser in HTS [46, 47]. Likewise individual reports ontherapy with the Er:YAG laser in a ther-mal (non-ablative) mode still requireevaluation in controlled, randomizedstudies [48].

5.6 Non-ablative laser treatmentSilvia HohenleutnerLaser devicesFPDL (585 or 595 nm)

Mechanism of action The selective destruction of microvascu-larization in scar tissue is postulated as the main mechanism of action. Due to the wavelength-dependent selectivephotothermolysis with the target chro-mophore oxyhemoglobin coagulationnecrosis of the blood vessels develops,that via hypoperfusion and hypoxia is supposed to lead to the regression ofpathological scars Further, a reduction ofTGF-�1 expression and fibroblast proli-feration, up-regulation of MMP-13(collagenase 3), induction of fibroblastapoptosis and up-regulation of ERK (ex-tracelluar signal-regulated kinase) andp38 MAP kinase activity after the use ofFPDL have been reported [49, 50].

Side effectsPurpura persisting for seven to 14 days isobligatory. Depending on the energydensity employed and the pigmentation

Recommendation ablative lasertreatmentA treatment with the CO2 andEr:YAG laser can be recommended forno longer active HTS with niveau dif-ferences, bridge or contracture forma-tion. CO2 laser removal of keloids as mono-therapy is not recommended. In certain cases (small-based largekeloids/debulking) CO2 laser removalcan be combined with other measuressuch as corticosteroid injection, cryo-therapy, pressure therapy or radiationtherapy.

10 Guidelines


of the skin vesicles and crusts may occur.Longer persisting hyperpigmentation oc-curs particularly in darker skin types andare less frequent with use of the wave-length 595 nm than with 585 nm.

Response rate/recurrence rate Alster and Williams [51] report – with afollow-up period of six months and a re-latively small patient collective – a signi-ficant improvement of sternotomy scarswith respect to erythema, scar thickness,texture and pruritus in comparison to anuntreated control area. These resultscould not be reproduced in several subse-quent studies [52]; particularly the re-sults in some case-control studies did notdiffer from the untreated control groupsafter longer follow-up observation peri-ods [53, 54]. Due to the lack of untreated controls, toosmall case numbers, too short follow-upperiods, lack of differentiation betweenHTS and keloids or lack of informationon the age and activity of the scars, themajority of published studies do not pos-sess sufficient evidence [28, 55]. There is no comparability of the studiesbecause of differing laser parameters, treat-ment intervals or follow-up periods anddiffering target criteria (elevation, redness,pigmentation, pruritus, consistency of thescar) [43]. In summary, the improvementof 50 to 80 % after two treatments withthe FPDL stated in individual publicati-ons [56] does not appear realistic after re-viewing study data or in light of experi-ence in the clinical routine. A subjectiveimprovement of pruritus of active HTS aswell as a diminishment of redness can oc-casionally be observed during the course oftreatment. The evidence of existing care,nonetheless, cannot confirm true efficacywith respect to these parameters as oppo-sed to the spontaneous course of HTS.

PerformanceTreatment with the 585 nm FPDL is per-formed depending on the degree of pig-mentation of the skin usually with energydensity of about 5.5–7,5 J/cm2 with a spotdiameter of 5–7 mm or with about 4.5–5.5 J/cm2 with a spot size of 10 mm. Atleast a two-time treatment at an interval ofabout six to eight weeks is recommended.

OtherHaedersdal [57] reports in a randomi-zed, controlled study of improvement ofscar texture in burn scars or mesh grafts

after burn injuries with a non-ablativefractional Er:glass laser. Sufficient experi-ence does not yet exist for HTS.

5.7 Radiation therapyRenato G. PanizzonMechanism of action Ionizing radiation has two effects on pa-thological scars: 1) an antiproliferativeeffect due to inhibition of new cell formation by delay of mitosis or the mitosis-induced cell death. Dose effects,the impact of fractionating, the oxygeneffect and the biological activity of diffe-rent qualities of radiation are also invol-ved. 2) an antiinflammatory effect due to lymphocyte apoptosis, induction ofdifferentiation of fibroblasts/fibrocytes,the effects on the cell membrane, endo-thelial cells or macrophages/monocytesas well as the effect on leukocyte adhe-sion (ICAM) and the oligonucleotides(NF�B). The result is a hypocellular, po-orly vascularized and hypoxic tissue withless excessive new formation of fibrob-lasts and finally inhibition of keloid de-velopment. An adequate radiation doserestores the balance between scar forma-tion and excessive cell growth withoutdelaying wound healing.

Side effects Erythema and scaling are seen as anacute side effect for several weeks in theirradiated field; these regress during thefurther course. In this phase hydratingcreams and sun protection are recom-mended as topical measures. At total do-ses between 10 and 20 Gy local pigmen-tation will develop up to one year afterirradiation (therefore sun protection!)that does, however, regress. Chronic ef-fects are hyper- and depigmentation,dryness of the skin and telangiectases,that are rare at total doses less than 12 Gy(which is why dermatologists recom-mend a total dose not over 12 Gy!).

Response rate/recurrence rate Through postoperative radiation ofkeloids with total doses between eight

Recommendation non-ablative lasertreatmentTreatment with FPDL can be recom-mended especially for reduction oferythema, e.g. in fresh, highly vascula-rized, red scars. Treatment with FPDL can be conside-red to alleviate severe pruritus.

and 30 Gy freedom from recurrence after12–24 months from 79 to 92 % could beachieved [58–60]. In exclusive irradia-tion of 15 keloids with 9–18 Gy, Doorn-bos et al. [61] report freedom from re-currence after 12 months in 73 % ofcases.

PerformancePostoperative radiation therapy after excision of a keloid should commencewithin 24 hours. A total dose of usually12 Gy in six or ten fractions of 2 Gy ap-plied daily or every second day is recom-mended. The selection of radiation type,i.e. a conventional radiotherapy (RT),brachytherapy or electron therapy orfractionating should be made individu-ally by the treating radiation therapist.

OtherTreatment should preferentially be per-formed in specialized clinics with inter-disciplinary consultation (dermatology,surgery, nuclear medicine).

5.8 Silicone sheets and silicone gelKlaus FritzMechanism of action The mechanism of action of silicone gelshas not been definitely clarified. Occlu-sion and the resulting increased moistureespecially of the stratum corneum is pre-sumed to have a signal effect on fibrob-lasts through cytokine release by kerati-nocytes [62]. Under application after 24 weeks a reduction of mast cells anddecreased expression of the Fas antigenin intralesional fibroblasts are seen [63].

Side effects Foils and cushions can be annoying touse. Gels and creams are usually well-to-lerated.

Response rate/recurrence rateIn a Cochrane Review the benefit of sili-cone use in scar prevention in patients

Recommendation radiation therapy Therapy of HTS with irradiation isnot recommended. Therapy of keloids with irradiationcan be recommended as monotherapyin individual cases. Irradiation following surgical therapyof keloids can be recommended. Postoperative irradiation as preventionof the de novo development of HTS orkeloids is not recommended.

Guidelines 11


with a predisposition to developingkeloids after surgery was confirmed (RR 0.46, 95 % CI 0.21 to 0.98). In thetreatment of scars with silicone sheetselasticity could be significantly improved(RR 8.60, 95 % CI 2.55 to 29.02). Thestudy quality in all studies was unfortun-ately very low [40].

Performance Silicones are available as gels, creams,cushions, sheets and foils. They areusually employed 12–24 h/day over 12–24 weeks.

OtherSilicone products offer the advantage ofpainless treatment and are usually easy touse

5.9 Extractum cepae (onion extract)Gerd GauglitzMechanism of action Extractum cepae acts in an antiinflam-matory manner, is bactericidal and inhi-bits fibroblast proliferation. As possiblemechanisms the induction of matrix me-talloproteinase I (MMP-I) [64] as well asan inhibition of the TGF-�/Smad signa-ling pathway [65] are discussed.

Side effects Side effects of scar gels containing onionextract are rare. In the event of intole-rance of ingredients of the ointment all-ergic contact dermatitis can develop.

Response rate/recurrence rateStudy data on the efficacy of extractumcepae for prevention and treatment ofHTS or keloids is inconsistent and thequality of the studies is poor overall. For prevention of HTS and keloids a prospective, randomized, controlled,non-blinded study on children with sur-gery on the thorax after 6-month use of ascar gel containing an onion extract a lessfrequent development of excessive scars

Recommendation silicone sheetsand silicone gelTreatment with silicone products canparticularly be considered as additionaltherapy in active HTS. The use of silicone products postope-ratively for prevention of de novo de-velopment of HTS or keloids in pati-ents at risk/with a predisposition aswell as after surgical therapy of HTSand/or keloids can be recommended.

than in the untreated comparison groupwas observed [66]. The therapy in thecomparative group remains largely un-clear with the statement “normal woundtherapy”. This is of particular signifi-cance, as in a further comparative studyon improving scar quality (erythema, pr-uritus, burning, pain, hypertrophy) bet-ween scar gels containing onion extractand a topical agent based on petrolatuma specific effect of the ingredients couldnot be proven [67]. It must be considered, however, that thepatient number in this study was low onthe whole, the operations were not onspecific predilection sites such as e.g. thethorax, and thus statistically significantresults could have been expected onlywith very high patient numbers. For treatment of HTS and keloids thebenefit of a combination of intralesionaltriamcinolone and an onion extract gelwas reported as positive, with both mo-notherapy with triamcinolone alone aswell as the combination with an additio-nal topical agent containing onion skinextract resulted in statistically significantimprovement. A calculation of statisticalsignificance with respect to the differen-ces of the therapy concepts was, no-netheless, not done in the study [68].

Performance Topical application should usually beperformed several times daily with mildmassage of the scar tissue. In hard, oldscars use under occlusion can also beconsidered. In prophylactic postopera-tive use, treatment can be started shortlyafter removal of sutures. In the treatmentof open wounds prophylaxis should bedelayed until complete epithelializationof the wound. Treatment usually conti-nues over several weeks to months.

Other The use offers the advantage of a painlesstreatment and is usually easy to use. The preparations with extractum cepaeusually contain other ingredients.

Recommendation extractum cepae(onion extract)Therapy of active HTS with combina-tion preparations containing extrac-tum cepae (onion extract) can be con-sidered as an additional therapy. The use of combination preparationscontaining extractum cepae (onion

5.10 5-fluorouracilGerd GauglitzMechanism of action Since 1989 5-fluorouracil (5-FU) hasbeen used particularly in the USA fortreatment of keloids. The agent 5-FU in-hibits the proliferation of fibroblasts as apyrimidine analog.

Side effects Pain at injection, hyperpigmentation,skin irritation and ulceration. Listedcontraindications are among others anemia, leukopenia, thrombocytopenia,pregnancy, bone marrow depression andinfection. Systemic side effects have notbeen observed to date

Efficacy The response rate in keloids is about 50 % [69]. Recent studies have demon-strated that even lower concentrations of5-FU in combination with intralesionalcorticosteroids can effectively reduce therecurrence rate after surgical removal ofear keloids [70]. In a prospective, rando-mized study with 10 patients with un-treated hypertrophic or keloidal sterno-tomy scars all four different treatmentregimens (dye laser, intralesional triamci-nolone, intralesional 5-FU and combi-nation) resulted in significant improve-ment of the scar. Significant differencesin efficacy between the individualtherapy approaches were not found, withthe triamcinolone group having side ef-fects of longer persistence [71]. Strictlyintralesional injection of a combinationof 5-FU (50 mg/ml) and triamcinoloneacetonide (TAC) (40 mg/ml) (1:3) forthe treatment keloids was examined in aretrospective study with either 5-FU/TAC/excision or TAC/excision in a totalof 102 patients, with the combination of 5-FU/ TAC/excision proving superiorto the combination TAC/excision [72].In a prospective study with a total of 69 patients the combination of TAC (40 mg/ml):5-FU 50 mg/ml) (1:9) onceweekly for two months injected strictlyintralesionally and in part additional use of a dye laser was shown to be super-ior to exclusive weekly injection of TAC

extract) for postoperative prophylaxisof de novo development of HTS orkeloids as well as for prevention of re-currence after surgical therapy of aHTS/a keloid can be considered.

12 Guidelines


40 mg/ml [73]. In a further double-blind, prospective study on 40 patientswith keloids and HTS better results withrespect to reduction of size and rednesswere seen with the combination TAC(40 mg/ml):5-FU (50 mg/ml) (1:9) in comparison to the injection of TAC40 mg/ml alone [74].

Performance At the start of treatment as well as afterfour injections a blood count should be done. Injections are done once weeklyin a concentration of 50 mg/ml and a total dose of maximally 50–150 mg pertreatment. Up to 16 injections can beperformed [75].

Other The treatment is off-label.

6 Further therapy approaches 6.1 InterferonJoachim FluhrMechanism of action Interferon-alpha (IF-�) and interferon-gamma (IF-�) reduce the overproduc-tion of type I/III collagen synthesis aswell as the production of glycosamino-glycans in the scar-forming fibroblasts.IF-�2b in addition to this increases the activity of collagenase and reducesangiogenesis.

Side effects IF can easily induce flu-like symptoms,mild pain as well as inflammatory reac-tions at the injection site.

Response rate/recurrence rateThe response rate of intralesional mono-therapy with IF-� and IF-� lies betweenabout 20 to 68 % as well as abut 80 % incombination with TAC. In controlled,prospective studies the efficacy of the in-jections was not always significant. Studydata do not allow for definitive evalua-tion for the treatment of HTS andkeloids [76].

Recommendation 5-fluorouracilTreatment of HTS with 5-FU is notrecommended. Treatment of therapy-refractory keloidswith 5-FU can be considered. For prevention of de novo develop-ment of recurrence after surgicaltherapy treatment with 5-FU is not re-commended.

Performance The injection of IF-�2b is intralesionalusually with a two-time procedure at aninterval of four to seven days. As preven-tion of a recurrence the injection can bemade on the day of surgery. In a combi-nation study with TAC 0.5 million unitsof IF-�2b per cm2 were injected in com-bination with TAC twice weekly [77].

Other Interferon has no license for the treat-ment of keloids in Germany/Austria(off-label use). The therapy is costly.

6.2 Calcium channel blockers,imiquimod, bleomycin

7 Authors/validity The current version of the guideline is anupdate of the guideline of 2004. Date completed: September 2011 untilApril 2012Level: 2kNext revision planned: June 2015 ICD-10 number: L91.0This guideline is a joint project of theGerman Society of Dermatology (DDG)and the Professional Association of Ger-man Dermatologists (BVDD) with par-ticipation of the Austrian Society of Der-matology and Venereology (ÖGDV),the German Society for Dermatosurgery(DGDC), the Austrian Society for Der-matosurgery (ÖGDC), the German So-ciety for Dermopharmacy (DG) and theSwiss Society of Dermatology and Vene-reology (SGDV). The project was finan-ced by the sponsor association of theDDG. With exception of travel costs theexperts received no financial support.

Recommendation calcium channelblockers, imiquimod, bleomycinA recommendation for or against theuse of calcium channel blockers, imi-quimod or bleomycin cannot be madeat present due to the small amount ofas well as often contradictory data.

Recommendation interferonTreatment of HTS and keloids withinterferons as monotherapy cannot berecommended at present. Treatment of keloids and HTS withinterferons in combination with TACcan be considered in individual casesin which other therapy options werenot sufficiently successful.

The guideline was developed in editorialindependence; the sponsor had no influ-ence. The guidelines group was free in itsdecisions. The conflicts of interest weredeclared in accordance to the stipulati-ons of the AWMF.

7.1 Declarations on conflicts of interest

See exhaustive account under keloid gui-deline (Keloidleitlinie): www.awmf.org

Correspondence to PD Dr. Alexander NastDepartment of Dermatology, Venereology and Allergology Charité – Universitätsmedizin BerlinCharité Campus Mitte Charitéplatz 1D-10117 Berlin, GermanyTel.: +49-30-450-518-313Fax: +49-30-450-518-977E-mail: [email protected]

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