Evaluating Tamoxifen Effect in the Prevention of Hypertrophic Scars Following Surgical Incisions

SEYED REZA MOUSAVI, MD, MOHAMAD RAAISZADEH, MD, MOHAMAD AMINSERESHT, MD, SHAHIN BEHJOO, MD
AND

OBJECTIVES

To evaluate the clinical utility of tamoxifen in the prevention of hypertrophic scars (HTSs).

MATERIAL AND METHODS In a double-blind randomized clinical trial, 300 patients with a history of HTSs who underwent surgery with different skin incisions were assigned randomly to two groups. The first received tamoxifen tablets postoperatively according to a standard protocol, and the control group received placebo. After 2 months, the two groups were compared according to the development of HTSs, and the results were analyzed. RESULTS The studied population comprised 235 men (78.7%) and 65 women (21.7%) who developed HTSs after surgical incision, 138 of whom (92%) were in the study group and 78 (52%) in the control group. CONCLUSION Tamoxifen seems to be an effective agent in the prevention of HTSs after surgery.

The authors have indicated no significant interest with commercial supporters.

ypertrophic scars (HTSs) represent an overabundance of fibroplasia in the dermal healing process. HTSs raise above skin level but stay within the confines of the original wound (in contrast to keloid, which are more aggressive and extend beyond the border of the original wound).1

Although HTSs do not cause significant morbidity or mortality, they are associated with major psychological and socioeconomic consequences.3 The exact underlying mechanism of HTSs is unknown, although the immune system is thought to be involved in the process, because scar tissue keratinocytes express human leukocyte antigen-2 and inter-cellular adhesion molecule-1 receptors, whereas keratinocytes in normal wound tissue do not.4 HTSs are rarely elevated more than 4 mm above the skin edge and occur frequently in darker pigmentedskin individuals aged 20 to 40, usually in the presternal, deltoid, and flexor regions across areas of tension. HTSs almost never involve areas such as the genitalia, eyelids, palms of the hand, or soles of the feet.5,6 Because the underlying mechanism causing the disease is unknown, many different treatment modalities have been employed without consistent success, including surgical excision, intralesional corticosteroids, radiotherapy, external compression, topical

A HTS is a hard, prominent, hypervascular lesion with a nodular and erythematous surface, usually occurring at areas of skin thickening. HTSs usually evolve after 8 weeks across areas of skin tension, burns, wound infections, hypoxia, or other dermal insult.1 The natural history of HTSs usually involves a period of rapid growth that may last for 6 months and then a regression phase over 12 to 18 consecutive months.2 Rapid growth potential of HTSs is an important matter that dictates timely diagnosis and proper management. In addition to unsightly appearance, HTSs may cause pain, pruritus, contracture, and organ dysfunction that may be refractory to treatment.

All authors are affiliated with Department of Surgery, Shahid Beheshti University of Medical Sciences, Shohada Tahrish

Hospital, Tehran, Iran

& 2010 by the American Society for Dermatologic Surgery, Inc.  Published by Wiley Periodicals, Inc.  ISSN: 1076-0512  Dermatol Surg 2010;36:665669  DOI: 10.1111/j.1524-4725.2010.01526.x
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medications, cryotherapy, laser, and low doses of enalapril.6 Leventhal and colleagues6 reviewed 70 treatment modalities published in the literature up to 2006 in a meta-analysis and estimated the overall success rate to be approximately 60%, with no statistically significant difference between different therapies. They concluded that there was no generally accepted therapeutic regimen. Therefore, primary prevention is regarded as an important and essential step in controlling the disease. Several studies have shown that tamoxifen can affect fibroblast growth patterns. In 1993, Grainger and colleagues7 showed that oral tamoxifen may decrease smooth muscle proliferation in rats, probably due to prolonged mitosis in the G2 through M phases.7 In 1998 Hu and colleagues reported surgical and medical therapies to be ineffective in controlling HTSs and demonstrated that tamoxifen can inhibit fibroblast proliferation in biopsy specimen cultures from keloids.8 In 2001, Mikulec and colleagues found that keloid fibroblasts produce more transforming growth factor beta (TGF-b) than with fetal fibroblasts and that tamoxifen uptake by these cells decreases TGF-b production. He concluded that the addition of tamoxifen corrects wound healing process by decreasing TGF-b production.9 A study by Zhu to evaluate the efficacy of tamoxifen in suppressing fibroblast proliferation and TGF-b production showed that this regimen suppresses fibroblast activity in Dupuytren fascia and reduces TGF-b levels in fibroblasts.10 A study by del Peso and colleagues in 2003 evaluating the effect of tamoxifen in retroperitoneal fibrosis syndrome showed this drug to be effective.11 In 2003, Tau and colleagues compared the effects of tamoxifen and corticosteroids in the treatment of

patients with idiopathic retroperitoneal fibrosis and showed that tamoxifen therapy is associated with better outcomes in terms of treatment duration and safety profile.12 In 2006, Ruffy and colleagues exposed mature dermal fibroblasts to different concentrations of tamoxifen and concluded that tamoxifen concentrations of 12 mg/mL delays cellular proliferation and decreases growth factors (basic fibroblast growth factor, vascular endothelial growth factor) and suggested that clinical use of tamoxifen may inhibit scar formation.13 Tamoxifen is a nonsteroidal agent that competitively inhibits estrogen receptors. Its half-life is 7 to 14 hours, and it is excreted by the liver. Because of anti-estrogenic effects, tamoxifen has been administered for estrogen receptorpositive breast cancer for decades; it is also used to treat progesterone-resistant endometrial cancer.14 The usual dose of tamoxifen has been 10 mg two times daily, with no significant toxic effects; adverse effects in usual doses are minor. Flushing is common, with nausea and urinary retention seen occasionally.15

Materials and Methods Despite the broad range of treatment modalities, there is none universally accepted in the use of oral tamoxifen. In a double-blind randomized clinical trial, 300 patients with a history of HTSs who underwent surgical operations with different skin incisions were assigned randomly to two groups. This study was done in Shohada Tajrish and Ayatollah Taleghani Medical Centers and confirmed complete related to the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975, as revised in 1983 in Tokyo. The patients were selected and assigned randomly to case and control groups.

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After informed consent was obtained and necessary instructions provided to the patients, primary patient data were recorded in questionnaires. One month after surgery, patients in the case group were given tamoxifen 10 mg two times daily for 2 months, and patients in the control group received placebo for the same duration. All patients were examined for HTS formation before treatment, then every 2 weeks, and finally after completion of the study. Neither the patients nor the examiner knew the study group of the subjects. Results were recorded in relevant data forms. We analyzed using two methods: objective and volume (extent and height from the adjacent healthy skin) estimated with millimeters. The drug used in our study is the generic name tamoxifen (C26H29NO) and the dose of therapy is 20 mg per day. Quantitative and qualitative variables were analyzed using t- and chi-square tests, respectively.

TABLE 1. Comparison of Width of Hypertrophic Scars of Two Groups

mm Study Group Tamoxifen Placebo After Treatment 510 410 Before Treatment 14 612

Discussion and Conclusion Keloids are benign fibroproliferative growths distinguished by excessive collagen deposition in the dermis. The exact etiology of these lesions is unknown. They are considered a derailment of the normal wound healing process, with a higher prevalence in darker pigmented skin. Keloids are often described as benign fibroproliferative growths resulting from a connective tissue response to a variety of insults, such as surgery, burns, trauma, inflammation, foreign-body reactions, and endocrine dysfunction, although they occasionally occur without apparent external cause. They are characterized by excessive collagen and glycosaminoglycan deposition within the dermis, an increase in collagen turnover, and microvasculature regeneration.1517 Clinically, keloids may not appear for several months and can be delayed for several years after initial injury. Minor injuries can produce a fairly large, deep, reddish-purple indurated lesion that rarely subsides. They can range in size from small papules a few millimeters in diameter to football size and larger. Their texture can vary between soft and dough-like to a hard and rubbery consistency. These lesions most commonly affect areas of skin tension. Rarely, keloids may develop on the palms of the hands, soles of the feet, and the genitalia.15 Keloid formation can be found in all ethnicities but has a higher predilection for darker-skinned people. Why occurrence rates are higher in these groups than in others is inconclusive. Inheritance patterns may offer clues as to who could be at greater risk of being predisposed to forming these types of lesions. Several reports have suggested that keloids follow an autosomal-dominant or autosomal-recessive inheritance pattern, although the exact mode of inheritance

Results The studied population comprised 235 men (78.7%) and 65 women (21.7%) who developed HTSs after surgery, 138 of whom (92%) were in the study group and 78 (52%) in the control group. Surgical incision sites was in the extremities (44.3%), torso (35%), and head and neck (20.7%). Sixty-four patients had a history of immunosuppressive drug consumption (21 in the case group and 43 in the control group). Ninety-eight patients had a history of dermatologic disorders (90 in the case group and 8 in the control group). Thirty-five patients in the case group and 15 controls had type I diabetes mellitus, and of the total 300 patients, 216 (72%) developed HTSs, including 138 in the case group (52%) and 78 controls (92%) (Table 1).

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remains unknown. Marneros and colleagues report observing 14 pedigrees with familial keloids that spanned three generations.16 Although most families in the study were African American, the report concludes that this may be associated more with ethnicity than skin pigment, because some lighterskinned members of the families had the more severe lesions. Through the use of a genome-wide linkage screen, plausible gene loci for these keloid pedigrees were identified.16 Their results found a pattern consistent with an autosomal-dominant mode of inheritance. Subsequent linkage analysis has revealed two distinct gene loci that may serve as specific susceptibility genes.18 In keloid lesions, the therapy chosen is predicated upon several factors, including size, location, and depth of lesion; age of patient; and past response to treatment. Surgical excision, radiation, pressure therapy, cryotherapy, intralesional injections of corticosteroids, interferon and fluorouracil, topical silicone and other dressings, and pulse-dye laser treatment have all been found to induce some degree of regression.19 In our study, 216 of 300 patients (72%) with a previous history of HTSs developed HTSs in the surgical site. Some other studies have reported different results. Considering different patient populations, different ethnicities, and specific incisions studied, comparison of the results is not possible, although it can be concluded that patients with a previous history of HTSs are more likely to develop them again. In our study, HTS formation in patients treated with tamoxifen immediately after surgery was significantly lower than in the control group (52% vs 92%). The above result is consistent with the findings of Hu and colleagues in 1998, suggesting a related inhibitory effect of tamoxifen on fibroblasts. Also, it supports Hu and colleagues theory suggesting an effect of tamoxifen in suppressing

fibroblast activity10 in Dupuytren fascia and decrement of TGF-b production.20 In 2001 Mikulec and colleagues showed that tamoxifen suppresses TGF-b production by keloid fibroblasts.9 Tamoxifen seems to be an effective agent in the prevention of HTSs after surgery (Table 1). In our study, there was no significant difference in HTS formation between men and women. The patient population was ethnically homogeneous, so it was not possible to determine and compare the incidence of HTSs in various races. Dermatologic disorders were significantly more common in the case group (60% vs 0.3%), where tamoxifen proved to be more effective (Table 1). Immunologic disorders were also more common in cases than in controls (40.7% vs 18.7%). Therefore, one can postulate that tamoxifen is more effective in patients with definite dermatologic pathology. According to the above findings, tamoxifen can be used as an effective and acceptable agent to prevent HTSs.

References
1. Joanna M. Zurodu: topical treatment of hypertrophic scar. J Am Acad Dermatol 2006;55:102431. 2. Leivis SK. Hypertrophic scar: a genetic hypothesis. Burns 1990;16:1769. 3. Niessen FB, Spauwen PH, Schalkwijk J, Kon M. On the nature of hypertrophic scar and keloid. Plast Reconstr Surg 1999;104:14358. 4. Brody GS, Peng ST, Landel RF. The etiology of hypertrophic scar contracture. Plast Reconstr Surg 1981;67:63784. 5. Iannellos, et al. Low dose enalapril in the treatment of surgical cutaneous hypertrophic scar and keloid-two case report and literature review. Med Gen Med 2006;8:6. 6. Leventhal D, Furr M, Reiter D. Treatment of keloid and hypertrophic scar: a meta-analysis and literature review. Arch Facial Plast Surg 2006;8:3628.

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7. Grainger DJ, Weissberg PL, Metcalfe JC. Tamoxifen decreases the rate of proliferation of rat vascular smooth-muscle cells in culture by inducing production of transforming growth factor beta. Biochem J 1993; 294(Pt 1):10912. 8. Hu D, Hughes MA, Cherry GW. Topical tamoxifen a potential therapeutic regimen in treating excessive dermal scarring? Br J Plast Surg 1998;51:4629. 9. Mikulec AA, Hanasono MM, Lum J, et al. Effect of tamoxifen on transforming growth factor beta 1 production by keloid and fetal fibroblasts. Arch Facial Plast Surg 2001;3:1114. 10. Hu D, Zhu X, Xu M, et al. The inhibitory effect of tamoxifen on human dermal fibroblast populated collagen lattices. Zhonghua Zheng Xing Wai Ke Za Zhi 2002;18:1602. 11. del Peso G, Bajo MA, Gil F, et al. Clinical experience with tamoxifen in peritoneal fibrosing syndromes. Adv Perit Dial 2003;19:325. 12. Tan M, Uygur MC, Diker Y, Erol D. Remission of idiopathic retroperitoneal fibrosis after sequential therapy with corticosteroids and tamoxifen. Urol Int 2003;71:4269. 13. Ruffy MB, Iannello S, Milazzo P, et al. Effect of tamoxifen on normal human dermal fibroblast. Arch Facial Plast Surg 2006;8:32932. 14. Chrousos G, Zoumakix E, Gravanis A. The gonadal hormones & inhibitors. Mol Hum Reprod 1999;5:78996.

15. Maarouf M, Schleicher U, Schmachtenberg A, Ammon J. Radiotherapy in the management of keloids. Clinical experience with electron beam irradiation and comparison with X-ray therapy. Strahlenther Onkol 2002;178:3305. 16. Marneros AG, Norris JE, Watanabe S, et al. Genome scans provide evidence for keloid susceptibility loci on chromosomes 2q23 and 7p11. J Invest Dermatol 2004;122:112632. 17. Botwood N, Lewanski C, Lowdell C. The risks of treating keloids with radiotherapy. Br J Radiol 1999;72:12224. 18. Dinh Q, Veness M, Richards S. Role of adjuvant radiotherapy in recurrent earlobe keloids. Australas J Dermatol 2004;45:1626. 19. Ragoowansi R, Cornes PG, Moss AL, Glees JP. Treatment of keloids by surgical excision and immediate postoperative singlefraction radiotherapy. Plast Reconstr Surg 2003;111:18539. 20. Kuhn MA, Wang X, Payne WG, Ko F, Robson MC. Tamoxifen decreases fibroblast function and downregulates TGF(beta2) in Dupuytrens affected palmar fascia. J Surg Res 2002;103:14652.

Address correspondence and reprint requests to: Seyed Reza Mousavi, MD, Professor of Vascular and Trauma Surgery; Shahid Beheshti University of Medical Sciences, Tehran, Iran, or e-mail: seyed29@yahoo.com

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