Current developments and uses of cryosurgery in the treatment of keloids and hypertrophic scars CHRISTOS C. ZOUBOULIS, DrMed; EFTICHIA ZOURIDAKI, DrMed; ALINA ROSENBERGER, DrMed; ANNETTE DALKOWSKI, DrMed Cryosurgery is currently regarded as the treatment of choice for keloids and hypertrophic scars. Four techniques are established or currently under evaluation in this area. The first is cryosurgery as monotherapy. Using this regimen, 241 of 356 patients (68%) with keloids and 72 of 89 patients with hypertrophic scars (81%), showed a greater than 50% improvement or complete regression (five studies). Using the second technique, cryosurgery with intralesional corticosteroids, significant regression of keloids was found in 119 of 159 patients (75%; four studies). Cryosurgery induces tissue edema and facilitates intralesional injections; however, the combined therapy was not superior (90% greater than 50% reduction of lesional volume) to monotherapy (83.3%) in a study of 40 patients with keloids. The third technique is surgical debulkment prior to cryosurgery without corticosteroids. This regimen is unavoidable in large keloids; however, it can result in recurrences despite its shortterm promising effects. Intralesional cryosurgery, the fourth technique, was developed by modifying the technique by Weshahy and is under evaluation in our department. In addition, histological and immunohistological studies of keloids and keloidal fibroblasts in vitro treated by cryosurgery have detected changes indicating potential rejuvenation of the scars. From the Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, Berlin, Germany Reprint requests: Prof. Dr. Christos C. Zouboulis, Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, Fabeckstrasse 60–62, 14195 Berlin, Germany. Fax: + 49-30-84456908; Email: [email protected]. Copyright Ó 2002 by The Wound Healing Society. ISSN: 1067-1927 $15.00 + 0 98 Cryosurgery—the well-aimed and controlled destruction of diseased tissue by application of cold—is an effective and efficient method for treating various skin diseases.1–3 The technique has several advantages2 and, especially in the treatment of keloids and hypertrophic scars, provides good therapeutic and cosmetic results with few contraindications and a low incidence of complications.4–7 The therapeutic properties of tissue freezing have also been used successfully to treat superficial atrophic acne scars.8,9 CRYOBIOLOGICAL BACKGROUND The biological changes that occur in cryosurgery have been studied in vitro and in vivo and are caused by a reduction of tissue temperature and consequent freezing (reviewed in4,10,11). Tissue injury is induced by direct physical effects of cell freezing and by the vascular stasis that develops in the tissue after thawing. The cryoreaction is therefore characterized by the physical and vascular phases. A postulated third phase of cryoreaction, the immunologic phase, is still under investigation. Factors affecting the effects of freezing on tissue and their optimal parameters for the treatment of keloids and hypertrophic scars are listed in Table 1. Cryosurgical instrumentation Currently, there are many commercially available, wellfunctioning cryosurgical units with variable design, function, and performance characteristics.4,12,13 Sufficient cold for cryosugery can be produced by direct or indirect application of a solid or liquid cryogen stored at low temperatures, by lowering the pressure of a gas (JouleThompson effect), electromechanically, or simply by refrigeration. The devices are mainly characterized according to the cryogen applied and the manner of cryogen application to the skin. WOUND REPAIR AND REGENERATION VOL. 10, NO. 2 ZOUBOULIS, ET AL. Table 1. Factors affecting the effects of freezing in tissue Factor Speed of tissue freezing Speed of thawing Intra-/extracellular osmotic phenomena Probe tip temperature Tissue temperature Duration of freezing Repetition of freeze-thaw cycles Vascular reaction Immunologic reaction Optimum parameters* Moderate speed (up to 100°C/min) Slow speed (10°C/min, sponaneous rewarming) Heterogenous and homogenous nucleation )85°C to )190°C )20°C to )25°C 30 seconds No Yes Probable *These parameters are optimized for treatment of keloids and hypertrophic scars. Clinical development of cryoreaction The physical clinical course of the cryoreaction starts with the whitish frozen phase followed by a peripheral erythema, occurring immediately to 30 minutes after cryosurgery.4,10 The treated area becomes edematous between a few minutes and a few hours after the procedure, and a bulla is usually formed 1 to 3 days later. Consequently, exudation lasts between a few days to 14 days after cryosurgery followed by mumification of the lesion, whereas a serum crust is built from the second to the fourth post-treatment week. Finally, the healed area presents a slightly atrophic, cosmetically acceptable, initially erythematous scar. To minimize erythema and edema occurring after cryosurgery, a mild, nonatrophogenic steroid cream (e.g., hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone-17-butyrate, methylprednisolone acetate, prednicarbate) can be applied to the lesion immediately after treatment, especially in areas that usually react with strong edema (i.e., facial area). The bulla serous content is aspirated with a sterile 99 fine needle 48 hours after treatment, whereas the bulla roof is left on the lesion as a natural protective film. A disinfectant-drying solution (e.g., Castellani colorless solution, merbromine 2%, povidone-iodine 10%) or lotion (e.g., chlorhexidine 1% in lotio alba aquosa) is then prescribed for use once daily. CRYOSURGERY IN THE TREATMENT OF KELOIDS AND HYPERTROPHIC SCARS Cryosurgery is indicated for diverse benign and premalignant lesions and for selected malignant skin tumors.1–3,14 The method is considered the treatment of choice or a valuable alternative treatment in several skin diseases. Any area of the body can be treated, and there are no age limitations. If the therapeutic result is not sufficient after the first session, cryosurgical treatment can be repeated as required every 20 to 30 days. Topical anesthesia is usually not required. Cryosurgery was found effective and safe in keloids and hypertrophic scars in several studies performed over the past few years (Table 2). Because of its major advantage of rare recurrences, this technique, used either as monotherapy or in combination, has been established as the treatment of choice for keloids and hypertrophic scars.2,4 Effects of freezing on the connective tissue An advantage of cryosurgery often cited is that of minimal scarring. The collagen fiber network of the dermis has been shown to remain largely undamaged by the standard cryosurgical procedures performed by clinicians.15 Using the young domestic pig as a model and two 1-minute freezethaw cycles, no alteration in the periodicity of fibrillar Table 2. Cryosurgery of keloids and hypertrophic scars: clinical results Treatment Lesion Study Number of patients Significant-tocomplete remission % Recurrences Cryosurgery as monotherapy Keloids Mende [24] Zouboulis et al. [5] Rusciani et al. [6] Ernst & Hundeiker [7] Zouridaki et al. [21] Total 7 55 40 234 20 356 5 28 34 158 16 241 71 51 85 68 80 68 – – – 9 – 9 (2%)* Hypertrophic scar Zouboulis et al. [5] Ernst & Hundeiker [7] Total 38 51 89 29 43 72 76 84 81 – 2 2 (2%) Keloids Hirshowitz et al. [28] Ernst & Hundeiker [7] Zouridaki et al. [21] Banfalvi et al. [29] Total 58 56 20 25 159 41 38 19 21 119 71 68 95 84 75 9 2 – – 11 (7%) Cryosurgery combined with intralesional corticosteroids *Valves indicate recurrances as percent of total number of patients. 100 ZOUBOULIS, ET AL. cross-banding and no fracturing or distortion of collagen fibrils were found. In another study on rats, wound contraction after freeze injury was minimal in contrast to burn damage, in which contracture was the rule.16 Effects of freezing on keloid fibroblasts Fibroblasts are rather resistant to freezing.15,17 Cryosurgery was shown to increase their proliferation in vivo18 and, in keloid fibroblast cultures from some but not all patients, in vitro.17,19 Furthermore, cryosurgery induced synthesis of collagen III and, consequently, an enhanced collagen III/ collagen I ratio in keloid fibroblasts, but not in normal ones in vitro. In addition to these effects, alterations in a-smooth muscle actin and tenascin C expression were detected.20 Therefore, cryosurgery appears to affect differentiation of keloid fibroblasts toward normalization of their phenotype. Structural changes in keloids and hypertrophic scars after cryosurgery Significant skin thickening was found to occur 3 weeks after cryosurgery of pig skin, which was consistent with an increase in the number of fibroblasts followed by significant thinning at 6 months, probably due to the chronic ischemia induced by cryosurgery.15,18 In humans, neovascularization, regular linear arrangement of collagen bundles, increased fibroblasts in stroma running parallel to the skin surface, and mononuclear cells mostly arranged at the perivascular area were found in clinically responding lesions after cryosurgery.5 In a prospective, randomized study of 40 patients with keloids that compared the clinical and histological effects of cryosurgery as a single regimen or combined with intralesional steroids, increased vessel number and lumen dilatation in both groups and a WOUND REPAIR AND REGENERATION MARCH–APRIL 2002 reduction of the number and length of rete ridges in the monotherapy group were the major structural changes observed.21 Immunohistologically, enhancement and diffusion of tenascin C expression in the whole treated dermal region and depletion of interferon-c expression, indicating immune regulation, were found.22 These histological and immunohistological studies indicate that cryosurgery can induce changes in keloids that are compatible with rejuvenation of the scars. Cryosurgery as monotherapy Cryosurgery as a monotherapy regimen was first used by Shepherd and Dawber in 1982.23 They treated 17 patients with keloids with a single cryosurgical session, achieving 80% improvement of the lesions; however, they observed a high recurrence rate of 33%. With the exception of case or technical reports, further monotherapy studies were probably postponed because of this rather disappointing recurrence rate, until Mende,24 as well as Zouboulis and Orfanos,25 showed that repeated cryosurgical sessions can exhibit a beneficial effect on keloids and hypertrophic scars and prevent relapses. In the meantime, 241 of 356 patients with keloids (68%) and 72 of 89 patients with hypertrophic scars (81%) in several studies have shown a greater than 50% improvement or complete regression after cryosurgery5–7,21,24 (Figure 1). Acne keloids also showed a 73% improvement or complete regression in 16 patients treated.9 To achieve these results, 1 to more than 20 sessions lasting an average of 30 seconds each applied once monthly, using the contact method of treatment, were required. Progression or recurrence were rare (2%). The number of sessions and the duration of lesions significantly correlated with the result of the treatment, with more than three sessions and lesions of less than 2 years’ duration providing the best FIGURE 1. Hypertrophic scars after chemical burn with sulfuric acid and contraction of the right elbow joint. A 21-year-old male patient as seen before (a) and 1 year after (b) nine sessions beginning with liquid nitrogen (four sessions) and ending with nitrous oxide (five sessions), 30 seconds/lesion, contact technique. Elbow mobility is was completely attained. WOUND REPAIR AND REGENERATION VOL. 10, NO. 2 results. The age and sex of the patient, the size and location of the lesions, and pretreatment with another method did not influence the outcome of cryosurgical treatments.5 Cryosurgery was shown to exhibit significantly better results than intralesional triamcinolone (5 mg/lesion) in a randomized study of 11 patients with multiple acne keloids, especially in early, vascular lesions.26 Cryosurgery with intralesional corticosteroids Cryosurgery has been applied to the treatment of keloids and hypertrophic scars using a weak cryotherapy regimen prior to intralesional corticosteroids in order to induce tissue edema and facilitate intralesional injections.27 This procedure was advanced to a combination regimen by Hirshowitz et al.28 with the impressive result of 71% complete remission in 58 patients with keloids. In the meantime, the regimen exhibited significant regression of keloids in 119 of 159 patients (75%) treated in four studies.7,21,28,29 However, the combined therapy with intralesional triamcinolone (2 mg/cm2) was not found to be superior to cryosurgery alone in a randomized trial with 40 patients with keloids.21 Surgical debulkment prior to cryosurgery with or without intralesional corticosteroids Lesions refractory to cryosurgery, or cryosurgery combined with intralesional corticosteroids, can be surgically removed and postsurgical cryoprevention, with or without intralesional corticosteroids, can be applied to reduce recurrences. This regimen is unavoidable in large ZOUBOULIS, ET AL. 101 keloids30,31 (Figure 2). Intramarginal excision is advisable because it is followed by a lower recurrence rate when compared to extramarginal excision.32 Removal of the lesion by surgery or CO2 laser presents similar recurrence rates;33 however, CO2 laser provides a high degree of hemostasis and avoidance of sutures. Alternative cryosurgical approaches A method of intralesional cryosurgery for keloids and hypertrophic scars was developed by modification of the technique by Weshahy34 and is under evaluation in our department.4,11 The freezing peel (cryopeeling) is a full face, superficial cryosurgical treatment for atrophic acne scarring that is especially useful in patients with mild-to-moderate circinate scars. Results are similar to those obtained with chemical peeling, but not as good as those obtained with dermabrasion.35 If a mild regimen is chosen, repeated sessions, sometimes over 2 to 3 years, are required to obtain optimal results.36 COMPLICATIONS AND CONTRAINDICATIONS Cryosurgical treatment of keloids and hypertrophic scars is generally well tolerated, and only minor complications have been reported. Among the various temporary or permanent complications described after cryosurgery,1,2,8,14 local pain during and/or shortly after treatment and lesional hypopigmentation and/or peripheral hyperpigmentation FIGURE 2. Huge keloids at the neck and the earlobe (arrow) before (a) and after (b) intramarginal excision with the carbon dioxide laser under general anesthesia and intraoperative intralesional corticosteroid injections. This was followed by 12 sessions of cryoprevention (liquid nitrogen, 30 seconds per lesion, contact technique) and intralesional corticosteroids (triamcinolone, 2 mg/cm2 lesional surface). 102 ZOUBOULIS, ET AL. are the major side effects that occur when treating keloids and hypertrophic scars. About one-third of the patients treated complained of mild local pain, which was easily managed when necessary. Lesional hypopigmentation developed in 12% to 100% of the subjects, and skin atrophy in 1% to 8%. Single cases of large local edema, wound infection, local hypoesthesia, local necrosis, and formation of milia have been reported.5 Delayed wound healing is an additional side effect that mostly occurs after the combined regimen of cryosurgery with intralesional corticosteroids.21 These complications are dependent on the duration of freezing and the number of freeze-thaw cycles applied.5,6,24 There are a few absolute contraindications, including cold-inducible urticaria, cryoglobulinemia, cryofibrinogenemia, and Raynaud’s disease.1,2 Relative contraindications are collagen diseases and lesions at the extremities of elderly and black-skinned patients from long-term depigmentation attributable to melanocyte death. REFERENCES 1. Zouboulis CC, Blume-Peytavi U. Kryotherapeutische verfahren in der dermatologie. Kassenarzt 1995;7:38–50. 2. Zouboulis CC. Cryosurgery in dermatology. Eur J Dermatol 1998;8:466–74. 3. Zouboulis CC. Kryochirurgie in der dermatologie: Stand der technik und neue methoden. In: Deutscher Ka¨lte- und Klimatechnischer Verein eV DKV, editor. DKV-Tagungsbericht Berlin 1999. 26. Jahrgang, Band I. Stuttgart: Kessler, 2000:13–24. 4. Zouboulis CC, Orfanos CE. Cryosurgical treatment. In: Harahap M, editor. Surgical techniques for cutaneous scar revision. New York: Marcel Dekker, 2000:185–234. 5. Zouboulis CC, Blume U, Bu¨ttner P, Orfanos CE. Outcomes of cryosurgery in keloids and hypertrophic scars. A prospective consecutive trial of case series. Arch Dermatol 1993;129:1146–51. 6. Rusciani L, Rossi G, Bono R. Use of cryotherapy in the treatment of keloids. J Dermatol Surg Oncol 1993;19:529–34. 7. Ernst K, Hundeiker M. Ergebnisse der kryochirurgie bei 394 patienten mit hypertrophen narben und keloiden. Hautarzt 1995;46:462–6. 8. Graham G. Cryosurgery for acne. In: Zacarian SA, editor. Cryosurgery for skin cancer and cutaneous disorders. St. Louis: Mosby, 1985:59–76. 9. 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