ORIGINAL ARTICLES

Combination of Surgery and Intralesional VerapamilInjection in the Treatment of the Keloid

Eray Copcu, MD,* Nazan Sivrioglu, MD,* Yucel Oztan, MD†

Keloid scars are one of the most challenging problems for physicians and surgeons. Thesescars have been treated in many ways, with varying success. Verapamil is a widely used cal-cium channel antagonist, and it has been shown that calcium channel blockers inhibit thesynthesis/secretion of extracellular matrix molecules, including collagen, glycosaminogly-cans, and fibronectin, and increase collagenase. In this study, we performed total keloid ex-cision in combination with reconstruction with W-plasty or skin grafting and injection ofverapamil hydrochloride into the lesions of 21 patients with keloids. Patients were followedfor minimum of 2 years, and the treatment outcome was evaluated based on the cosmeticappearances, symptomatic improvements, and the results of microscopic examinations. Also,patient satisfaction was scored with a visual analog scale. Two years after the operations,two patients had keloid in lesser diameter than the original lesions, two patients had lesionsthat were hypertrophic scars in appearance, and four patients had pruritus. One patient hadkeloid on the donor site. The rate of patient satisfaction was 6.4 on a scale of 1 to 10. Wereviewed the treatment of keloid in this study and obtained one of the lower rates of com-plication in the literature. We believe that surgical excision with W-plasty or skin graftingand intralesional verapamil injection may be a good alternative in the treatment of keloid.(J Burn Care Rehabil 2004;25:1–7)

Collagen synthesis and collagen degradation takeplace in a strictly controlled state of equilibrium.Loss of this equilibrium results in an abnormal tis-sue repair. Excessive collagen synthesis and/or fail-ure of collagen degradation may lead to one of themost challenging squeals in the clinical practice.Keloid and hypertrophic scars result from an exces-sive collagen deposition, although the exact causeis still unknown. The etiology of keloid remainsunclear, but genetic predisposition, pigmentedskin, and imbalances in hormonal levels1 are impli-cated. As cited in the review of Shaffer et al,2 thefirst study about the keloid was presented in 1806

and since then more than a thousand articles haveappeared in the literature about the pathogenesisand treatment of keloid. Nearly 200 years after thefirst study, treatment of this clinical condition isstill a challenge for dermatologists, plastic sur-geons, and physicians who give treat to scars. Ke-loids can be seen on all parts of the body. Generally,sternum and supradeltoid regions are the most af-fected parts, but also keloids of ears,3 penis,4 femalegenitalia,5 corneum,6 intraoral region,7 and plantarregion8 have been reported. Different treatmentmodalities also have been reported in the literature,but most of them had a high recurrence rate. Sur-gery is an old technique and has a high recurrencerate in the treatment of keloid.9 Lee et al10 firstreported the effect of verapamil on burn scars in theliterature. Verapamil is a widely used calcium chan-nel antagonist, and calcium channel blockers havebeen shown to inhibit synthesis/secretion of extra-cellular matrix molecules, including collagen, gly-cosaminoglycans, and fibronectin. In addition,they have been reported to increase collagenase andtransforming growth factor-� activity.11 Verapamilis a safe drug, and topical usage of this drug to treat

From the *Plastic and Reconstructive Surgery Department,Medical Faculty, Adnan Menderes University, Aydin, Turkey;and †Plastic and Reconstructive Surgery Department, AtaturkTraining Hospital, Izmir, Turkey.

Early results of this study were presented at International FirstEuropean Appointed XX National Congress held by the TurkishSociety of Plastic Surgeons in Istanbul, Turkey.

Address correspondence to H. Eray Copcu, MD, Medical Faculty,Plastic and Reconstructive Surgery Department, AdnanMenderes University, 09100 Aydin, Turkey.

Copyright © 2004 by the American Burn Association.0273-8481/2004

DOI: 10.1097/01.BCR.0000105097.36706.5D

1

Peyronie’s disease and Dupuytren’s contracturesalso has obtained successful results.11–13

PATIENTS AND METHODS

This study included 22 patients with keloids who weretreated with surgical excision and intralesional verapamilinjection and 1 patient who had hypertrophic scar afterblepharoplasty operation and who was treated with in-tralesional verapamil injection in Izmir Ataturk TrainingHospital and Adnan Menderes University Hospital. Pa-

tient data are summarized in Table 1. Keloids that werefusiform in shape and no more than 10 mm in widthwere excised and reconstructed with W-plasty, and full-or split-thickness skin grafts were preferred in wider le-sions. All specimens were examined pathologically. In-tralesional verapamil hydrochloride injections were per-formed intraoperatively and on days 7, 14, 28, andduring the second month after the operations. Intrale-sional verapamil injections to the donor sites were alsoperformed in patients who underwent skin grafting. Allpatients received 2.5 mg/ml of verapamil hydrochlo-

Figure 1. A. Preoperative view of the patient with sternum located keloid. Keloid excision and full-thickness skin grafting wereapplied. B. View of the patient 6 months after operation.

Table 1. Patient variables

No. Age Sex Localization Duration EtiologySurgical

Treatment Result Donor AreaPatient

Satisfaction

1 13 M Sternum 2 years Burn SSTG Good Good 82 20 F Sternum � deltoid 8 years Acne W-plasty Good None 73 16 F Sternum � deltoid 8 years Acne � vaccine W-plasty Good None 74 19 M Submandibular 1 year Incision W-plasty Moderate None 65 14 M Deltoid 9 months Vaccine W-plasty Excellent None 96 26 F Scapular 1 year Incision W-plasty Moderate None 57 17 M Cervical 2 years Burn W-plasty Good None 68 18 F Buccal 6 months Incision W-plasty Moderate None 69 34 F Trunk 2 years Burn STSG Good Good 8

10 18 M Deltoid 3 years Vaccine W plasty Poor (keloidformation)

None 4

11 23 F Trunk 2 years Incision FTSG Very poor (keloidformation)

Poor (keloidformation)

2

12 17 M Suprapubic 2 years Burn W-plasty Moderate None 713 23 F Sternum 1 year Incision FTSG Moderate Moderate 714 14 F Antebrachial 8 years Incision W-plasty Good None 715 19 F Cervical 1 year Incision W-plasty Moderate None 616 30 F Cervical 2 years Incision W-plasty Good None 817 18 F Antebrachial 3 years Incision W-plasty Moderate None 618 29 F Trunk 4 years Burn STSG Good Good 819 16 F Elbow 1 year Burn FTSG Good Good 820 27 M Trunk 2 years Incision FTSG Good Good 721 22 M Sternum 1 year Burn FTSG Poor Moderate 3

42 F Postblepharoplasty 15 days Surgical Injection alone Good

FTSG, full-Thickness skin graft; STSG, split-thickness skin graft.

Journal of Burn Care & Rehabilitation2 Copcu et al January/February 2004

ride, the doses of which varied from 0.5 to 5 ml depend-ing on the size of keloids. Other treatment modalities,such as pressure garments and silicone sheets were notused. All patients were examined 1, 2, and 6 months and2 years after the operations and recurrences, features oflesions, and symptoms were recorded (Figures 1–6).Lesions were classified according to their appearances asvery poor (rekeloid formation), poor (hypertrophic ap-pearances), moderate (visible scar), good (acceptablescar), and excellent (invisible scar). Also, a visual analogscale was used to determine patient satisfaction, and bi-opsies were performed in five patients to evaluate theresults 2 years after the operations.

RESULTS

All patients tolerated the surgical operations and in-jections well. There was no early or late complicationas a result of the procedures. The pathological exam-ination of excised specimens stained with Hematox-ylin and eosin showed keloid in all lesions. Six patientsnoted tolerable pain caused by injections. Verapamilinjection did not cause any side effects on the cardio-vascular system or other systems. One month after theoperations, all patients had scar formation, four pa-tients (18%) had scars hypertrophic in appearance,and only one patient who underwent full-thicknessskin graft had minimal keloid at the margins of thegraft. Two patients had scars hypertrophic in appear-Figure 2. Lateral view of the same patient 2 years

postoperatively.

Figure 3. A. Preoperative view of the patient with trunk located keloid. Keloid excision and split-thickness skin grafting wereapplied. B. One year after the operation.

Journal of Burn Care & RehabilitationVolume 25, Number 1 Copcu et al 3

ance at the donor side. Ten patients had pruritus. Sixmonths after the operations, six patients had scarsthat were hypertrophic in appearance on the keloidregion, one patient had keloid formation at the mar-gins of the graft, and one patient had keloid on thedonor site. Just six patients had pruritus. Finally, 2years after the operations, two patients had keloid inlesser diameter than the original lesions, two patientshad lesions that looked like hypertrophic scars, andfour patients had pruritus. One patient had keloid onthe donor site. Patient satisfaction with the outcomewas evaluated with a visual analog scale and scored as0 for dissatisfaction and 10 for full satisfaction. Theresults are presented in Table 1. Patient satisfactionvaried from 2 to 9, with an average of 6.4. Biopsy wasperformed in patients who had keloid on the opera-tion site and donor site. Microscopic examinationdemonstrated lesser collagen density and cellularity inthese cases. None of the patients underwent a secondoperation.

DISCUSSION

Despite recent advances in the understanding ofwound healing and scar formation, the treatment ofkeloid is still controversial. Although the combina-tion of surgery with intralesional steroid injections isconsidered as the best approach,14–17 many treat-ment alternatives were described in the literature withFigure 4. Donor site view of the same patient 1 year

postoperatively.

Figure 5. A. Preoperative view of the patient with deltoid region located keloid. Keloid excision and w-plasty were applied. B.View of the patient 6 months after operation.

Journal of Burn Care & Rehabilitation4 Copcu et al January/February 2004

varying recurrence rates. The treatment protocolswere summarized by Parker and include the follow-ing: excision (primary closure, local flap closure, ho-mograft closure, keloid skin closure), cryosurgery, la-ser (argon, carbon dioxide, Nd:YAG laser), radiationtherapy (primary, surgical adjuvant), steroids (intrale-sional, ointment, surgical adjuvant), pressure therapy,retinoic acid, penicillamine, colchicine, thiopeta, hy-aluronidase, vitamin E, silicone sheet or gel, and in-terferon (interferon-alfa-2b, interferon-�).9 Compar-isons of the treatment protocols are shown in Table 2.The pathogenesis of keloid includes excessiveamounts of collagen and other extracellular matrixcomponents.27 Abergel et al28 showed an abnormalcomposition and metabolism of collagen in keloidtissue in their study. Fibroblasts from the keloid tissuehave a greater amount of collagen type I, and whenstimulated, they show an exaggerated proliferation.29

Calcium channel blockers were first used in collagenmatrix on the connective tissue remodeling by Lee

and Ping in 1990.30 They reported that verapamilreduced the incorporation of tritiated proline into theextracellular matrices of the fibroblast-populated col-lagen matrix by almost 50 to 60%. Doong et al31

presented their observation about the calcium antag-onists and claimed that calcium antagonists depoly-merize actin filaments and alter the shape of fibroblastcells from bipolar to spherical and that this processresults in an increase in procollagenase production.Topical applications of verapamil were also used inPeyronie’s disease and Dupuytren’s contracture be-cause they affect the collagen metabolism. These ef-fects can be summarized as the following: Calciumantagonist increases collagenase activity of the extra-cellular matrix and decreases the synthesis and secre-tion of collagen and fibronectin, altering the fibro-blastic metabolism. Because the concentration ofverapamil required to induce the degradative re-sponse in fibroblasts in the laboratory exceeds the safeserum levels by 100-fold or more, only intralesionaltherapy is possible at present.13 The first successfulresults of the intralesional injection of verapamil werepresented in 1994 in burn scars.10 Lawrence32 pre-sented his experience with the intralesional verapamilinjection and pressure therapy in the treatment ofearlobe keloids and reported a cure rate of 55%.32

Finally, D’Andrea et al26 in their study in 2002 con-cluded that the treatment of keloids with perilesionalsurgical excision and topical silicone followed by anadjuvant treatment with intralesional verapamil hy-drochloride injection at certain intervals offered ahigher rate of resolution than other therapeutic strat-egies. In their study keloids were completely cured in54% of the cases. The cure rate in the present studywas greater than that in the study by D’Andreas,

Figure 6. Excised material of the same patient.

Table 2. Comparisons of treatment modalities and results

Author TreatmentPatient

No. Results

Borok et al18 Radiation 393 Cosmetic results excellent in 92%, favorable in 6%Hirshowitz et al19 Steroid 58 Complete regression (70.6%), improvement (13.7%), Recurrence (15.5%)Ohmori20 Silicone 46 Excellent (13%), good (47.8%), fair (26%), poor (13%)Henderson et al21 Laser 82 55% Excellent or good improvement (softening, flattening, lack of progression/

recurrence), 11% poorZouboulis et al22 Cryotherapy 93 61.3% had excellent or good results, 29% had poor response, 9.7% had no

responseFitzpatrick23 5 FU 100 Rare for a scar not to respondEspana et al24 Bleomycin 13 Complete flattening (42.8%)Conejo-Mir et al25 Interferon 30 66% did not recur (20/30)D’Andrea26 Surgery � silicone 22 Complete result (0), partial result (18%), absence of result (82%)D’Andrea26 Surgery � silicone

� verapamil22 Complete result (54%), partial result (36%), absence of result (9%)

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which revealed one of the most successful results inthe literature. However, we did not use the treatmentmodalities, such as topical corticosteroid or pressureapplication, but we performed W-plasty or grafting inwider lesions. The major advantages of these tech-niques were that there was no skin tension becausethe defects were closed free of tension after the exci-sion of keloids, but there also were disadvantages: thepossibility of keloid formation in the donor site in theskin grafting group and the possibility of W-shapedexcessive scarring in the other group. Fortunately, wehad just one patient with a W-shaped scar. We believethat the application of verapamil to the donor site wasa very valuable addition to the treatment of keloids.In particular, a female patient treated with split-thick-ness skin grafting had an excellent scar in the donorside without keloid or hypertrophic scarring (Figure4), and the postblepharoplasty patient was satisfiedwith the outcome in the early term. However, thesymptoms such as pruritus are very important in theclinic of the keloid, but most of the patients presentedto our clinic with esthetic disfiguring of their scars.The patient satisfaction is as important as the cure ofthe lesion. To our knowledge, there has been noother study in the literature that reported the rates ofpatient satisfaction. We speculated that an acceptableappearance of the lesions after the treatment and res-olution of pruritus are the most important criteria forthe patient satisfaction. Shaffer et al2 suggested thatfor any modality involving removal/debulking of akeloidal scar, a follow-up period of at least 12 months(and preferably 18 months) is needed to determinerecurrences. We followed the patients for minimumof 24 months. We hypothesized that a large propor-tion of the patients with keloid were not optimisticabout the treatment outcome before their admission.The high rate of satisfaction can be explained by thefact that we obtained acceptable results in the treat-ment of scars without keloid, although people be-lieved that the treatment outcome was not going tobe favorable.

CONCLUSIONS

No single technique has proven to be the definitivesolution, and combination therapies generally givebetter results than any single-treatment modality. Wespeculate that surgical excision with W-plasty or skingrafting and intralesional verapamil injection may bea good alternative for the treatment of keloids.

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