BJD. Summary. Patients and methods. British Journal of Dermatology DERMATOLOGICAL SURGERY AND LASERS

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1 DERMATOLOGICAL SURGERY AND LASERS BJD British Journal of Dermatology Effectiveness of combined pulsed dye and Q-switched ruby laser treatment for large to giant congenital melanocytic naevi E. Funayama, 1 S. Sasaki, 2 H. Furukawa, 1 T. Hayashi, 1 T. Yamao, 1 K. Takahashi, 1 Y. Yamamoto 1 and A. Oyama 1 1 Department of Plastic and Reconstructive Surgery, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo , Japan 2 Department of Plastic and Reconstructive Surgery, KKR Medical Centre, Tonan Hospital, Sapporo, Japan Summary Correspondence Akihiko Oyama. akihiko.oyama@mac.com Accepted for publication 10 May 2012 Funding sources None. Conflicts of interest None declared. DOI /j x Background There is no consensus on the most appropriate treatment for patients with large to giant congenital melanocytic naevi (CMN) because of the risk of melanoma development. Surgical excision followed by skin grafting or expanded skin coverage may cause unfavourable scarring. There is a balance to be achieved between minimizing the disfiguring appearance and the risk of malignant change. The pulsed dye laser (PDL) is commonly used for vascular lesions and is highly absorbed by melanin and haemoglobin. Its pulse duration is longer than that of Q-switched ruby lasers (QsRL), which can have nonspecific photothermolytic effects on surrounding nonpigmented naevus cells. Objectives To investigate the effectiveness of combined treatment with the PDL and QsRL for large to giant CMN. Methods Six patients with large to giant CMN were enrolled in this study. Treatment consisted of one pass of PDL treatment followed by one pass of QsRL treatment. Multiple rounds of treatment were applied to all patients. Results All patients responded to this combined regimen, and the lesional colour was effectively reduced. The mean number of rounds of laser treatment required to achieve skin lightening was 7Æ7. No patients suffered severe hypertrophic scarring. No cases of recurrence or malignant transformation were observed. The histological results from the patient who underwent the most laser therapy in this study showed a remarkable reduction in the number of melanocytic naevus cells after treatment. Conclusions This technique may enable the removal of most of the pigmented lesion and melanocytic naevus cells with minimal scarring. The management of large to giant congenital melanocytic naevi (CMN) remains controversial. Giant CMN are associated with an increased risk of melanoma development. While many treatment options are available, a consensus on the most appropriate strategy has not been achieved. Prophylactic excision may help reduce the risk of developing melanoma in patients with giant CMN. 1 However, for lesions of particular sizes and locations, complete removal is difficult. Furthermore, unfortunately, excisional treatment may result in scarring and deformity, which could affect a patient s quality of life. There is a balance to be achieved between minimizing the disfiguring appearance of the lesions and the risk of malignant change. The evolution of laser technology means that lasers could be a treatment option for CMN. In the past decade, several authors have used lasers to treat medium-sized or giant CMN. 2 9 Currently, it is common to use combinations of lasers, including normal-mode and Q-switched ruby lasers (QsRLs) 3 and resurfacing and Q-switched pigment-specific lasers. 6 8 The peak absorption of human melanin occurs at a wavelength of approximately 335 nm, and the absorption gradually declines with increasing wavelength. Here, we focused on the pulsed dye laser (PDL), which is commonly used for vascular lesions and which is highly absorbed by melanin and haemoglobin. In this study, we tested combined treatment with a PDL and a QsRL in six patients with large to giant CMN. This is the first report showing the effectiveness of a laser combination including a PDL. Patients and methods Between 1995 and 2010, a total of 42 cases of CMN (small to giant) were treated at Hokkaido University Hospital using a combination of PDL and QsRL. Among these cases were six 1085

2 1086 Combined pulsed dye and Qs-ruby laser treatment for CMN, E. Funayama et al. patients (two male, four female) with large to giant CMN covering more than 1% of the total body surface area who finished our laser treatment protocol course and have a known follow-up period. All were enrolled in this study. The locations and sizes of the lesions varied between the patients (Table 1). None of the patients had cerebral melanocytosis. Informed consent was obtained from all patients. All the patients underwent serial combination laser treatment using a PDL and QsRL under general anaesthesia every 3 6 months until maximum clearance. Each treatment consisted of a single pass of the PDL, followed by a single pass of the QsRL. This protocol was based on the results of a pilot study, which showed that PDL followed by QsRL was the most effective treatment for CMN (Fig. 1). The effectiveness of the PDL was first tested in cases 1 and 2, who were treated with the PDL alone before combination laser treatment was initiated. All patients underwent multiple rounds of treatment. Based on the residual pigmentation levels after combination laser treatment, solo QsRL treatment was performed several times in five cases (cases 1 5). The nodular lesions were excised surgically in three cases (cases 3, 5 and 7) because of the poor effectiveness of laser treatment and possible malignancy. A SPTL-1b PDL laser device (Candela Corp., Wayland, MA, U.S.A.) without dynamic cooling was used at a wavelength of 585 nm, a pulse duration of 450 ls, an energy fluence of 6Æ0 10Æ0 Jcm )2 and a shot diameter of 7 mm. An RD-1200 QsRL device (Spectrum Medical Technologies, Natick, MA, U.S.A.) was used at a wavelength of 694Æ3 nm, a pulse duration of 28 ns and an energy fluence of 6 10 J cm )2. The energy fluence was individualized according to the colour. The age of the patients at the first round of laser treatment ranged from 4 to 26 months. The clinical response at not < 6 months after the final treatment was evaluated using the 5-point scale established by Klimer et al.: 10 1 = poor (no change, with lightening of 25%); 2 = fair (slight improvement, with lightening of 16 50%); 3 = good (improvement, enabling differentiation from the surrounding healthy skin, Table 1 Clinical data and laser treatment results of six patients with large to giant congenital melanocytic naevi No. of treatments Complications Sex Age at primary treatment (months) % BSA Location PDL PDL + QsRL QsRL Further treatment Abnormal skin texture Others Results (score on 5-point scale) Malignant change 1 M Abdomen, HR (+) ()) 5 ()) leg 2 F 12 2 Nape (+) ()) 5 ()) 3 M 19 5 Chest 13 7 PE (+) ()) 5 ()) 4 F Leg HR a (+) ()) 4 ()) 5 F 24 1 Leg 4 3 PE (+) Hypopigmentation 4 ()) 6 F 4 5 Arm 9 Partially CO 2 laser (x1) (+) Hypopigmentation 5 ()) PDL, pulsed dye laser; QsRL, Q-switched ruby laser; BSA, body surface area; HR, hair removal; PE, partial excision. a This case is under treatment. Fig 1. A pilot study was performed to determine the order of laser treatment. A congenital melanocytic naevus on the chest in one patient was divided into four parts, and four laser treatment regimens were tested: pulsed dye laser (PDL) alone, PDL followed by Q-switched ruby laser (QsRL), QsRL followed by PDL and QsRL alone. Each laser procedure consisted of a single pass. PDL followed by QsRL was the most effective regimen. This case has not finished our laser-treatment protocol because the affected area is broad, and consequently was excluded from the study.

3 Combined pulsed dye and Qs-ruby laser treatment for CMN, E. Funayama et al with lightening of 51 75%); 4 = excellent (difficulty in differentiating the lesion from the surrounding healthy skin, with lightening of 76 95%); and 5 = clear (near-complete disappearance of the lesion, with lightening of 95%). We obtained biopsy specimens during the treatment of one patient (case 3). Consecutive histological findings are presented. Results None of the naevi showed complete clearance of pigmentation after a single round of treatment. Therefore, multiple rounds of treatment were needed in all patients (Table 1). All patients responded to the treatment regimen, and the lesional colour was effectively reduced. To make the treated areas similar in colour to the surrounding skin, at least four rounds of combination laser treatment (average 7Æ7) were required. In all patients, the naevi were only slightly visible after treatment (Figs 2 7). All patients were satisfied with the outcome, and the average improvement, assessed on a 5-point scale, was 4Æ5. No patients suffered severe scarring or obvious repigmentation. Re-epithelialization was completed within days after treatment. In two of the six cases, the lesions showed slight hypopigmentation after treatment. All cases showed abnormal skin textures of varying degrees. No other adverse effect was seen. Two patients had nodules within their CMN and underwent nodule excision. The nodule specimens were examined pathologically. None of the specimens was malignant. In case 3, who underwent the most laser therapy in this study (a total of 20 rounds of treatment), pathological studies were performed during sequential laser treatment. Repeated combination therapy gradually reduced the naevus cell number. The number of vessels also decreased. Fortunately, after the 16th round of treatment, no naevus cells were seen in the specimens, although histological skin atrophy (decreased dermal thickness), scarring in the dermis and the accumulation of melanin in the basal layer of the epidermis were observed. At this time, we obtained two specimens from the affected central area, neither of which showed residual naevus cells (Fig. 8). Discussion Ample evidence demonstrates that large CMN are precursors for the development of malignant melanoma However, the management of large CMN is controversial because of the lack of valid data regarding the incidence of malignant changes. A review published in reported that among 194 previously studied cases, there had been no new case of melanoma since an earlier review in At that time, three cases had been reported, of which two were central nervous system melanomas and one was a retroperitoneal melanoma. 16 This review estimated the combined lifetime risk of cutaneous and extracutaneous site melanomas at 2Æ3%. 16 Marghoob et al. 17 reported that the surgical removal of large CMN had a prophylactic effect on malignant melanoma, reducing the risk from 7Æ5% to 0Æ6%. Therefore, is surgical excision the best treatment for large CMN? Even after surgical treatment, malignant melanoma development might not be avoided. Streams et al. 18 reported a case of nonepidermal malignant melanoma arising from beneath a skin graft, and suggested that a deep naevus nest may have remained after the excision and developed into a malignant melanoma. Naevus cells may reside in the deep subcutaneous fat or even underlying muscle. 19,20 Given that complete removal of naevus cells is impossible, there may be no difference in underlying malignant potential between excision and laser treatment. 9 Some authors insist that the sheer number of melanocytes is responsible for the increased malignant potential. 9,21 The destruction of melanocytes using lasers may reduce the risk of melanoma in cases of large CMN. Horner et al. 2 affirmed that the sole aim of treatment should be the improvement of cosmesis on the basis of a previous report 21 showing a 29% recurrence following surgical excision in Fig 2. Case 1. A 12-month-old boy with a large congenital melanocytic naevus on his abdomen and both thighs who underwent combined pulsed dye laser plus Q-switched ruby laser treatment. Before treatment; 6 months after the last round of laser treatment.

4 1088 Combined pulsed dye and Qs-ruby laser treatment for CMN, E. Funayama et al. Fig 3. Case 2. A 12-month-old girl with a congenital melanocytic naevus on her nape who underwent combined pulsed dye laser plus Q-switched ruby laser treatment. Before treatment; 3 months after the ninth round of laser treatment. Fig 4. Case 3. A 19-month-old boy with a large congenital melanocytic naevus on his chest who underwent combined pulsed dye laser plus Q-switched ruby laser treatment. Before treatment; 1 year after the last round of treatment. Fig 5. Case 4. A 26-month-old girl with a large congenital melanocytic naevus on her right leg who underwent combined pulsed dye laser plus Q-switched ruby laser treatment. Before treatment; 8 months after the last round of treatment. patients with CMN. Considering the poor cosmetic results of surgical excision, laser therapy may be a good alternative. Another concern about laser treatment for CMN, the potential for laser-induced malignant transformation of naevus cells, remains. 22 It is a theoretical concern, however, and has not been found to be an issue in clinical practice. 8 Indeed, there is no evidence that any form of treatment of large CMN affects the risk of melanoma 2. Hafner et al. 23 reported that no major

5 Combined pulsed dye and Qs-ruby laser treatment for CMN, E. Funayama et al Fig 6. Case 5. A 24-month-old girl with a medium-sized congenital melanocytic naevus on her right lower leg who underwent combined pulsed dye laser plus Q-switched ruby laser treatment. A protuberant lesion was partially excised. Before treatment; 7 years after the last round of treatment. alteration in global gene expression or the expression of genes associated with malignant melanoma occurred in cultured neonatal melanocytes after QsRL laser exposure. The treatment goal is to remove as much of the naevus as possible while preserving function and improving cosmetic appearance. Numerous laser treatment options for CMN have been Fig 7. Case 6. A 4-month-old girl with a large congenital melanocytic naevus on her upper extremity who underwent combined pulsed dye laser plus Q-switched ruby laser treatment. After laser treatment, the patient underwent laser hair removal. Before treatment; 3 months after the last round of treatment. reported. 2 9 Although ablative lasers (e.g. CO 2 lasers) are effective for superficial intradermal naevi, Horner et al. 2 reported that half of the cases developed hypertrophic scarring. The introduction of short-pulse red and near-infrared lasers, including QsRL, alexandrite and neodymium yttrium aluminium garnet (Nd:YAG) lasers, has made it possible to treat various pigmented skin lesions without scarring. 3,6 8 Pigment-specific lasers provide relatively targeted treatment of pigment cells through photoacoustic and selective photothermolytic effects. 8 However, the results are not permanent, and the recurrence of pigmentation often occurs because of the persistence of melanocytes after the discontinuation of treatment. 5 The efficacy of quality-switched pigment-specific lasers is not thought to be sufficient for treating CMN because the pigmented nest is located deeper than the laser beam can reach, 4 and because of the persistence of naevus cells not containing melanin, 3,4 which can escape from pigment-specific laser treatment because of their lack of melanin and the high selectivity of the laser beam. In the present study, our laser protocol for large to giant CMN, which combined a PDL and a QsRL, produced better than expected results. Other patients, who had small to medium-sized CMN treated using our protocol showed similar results. This study demonstrated the efficacy of PDLs for CMN. PDLs, which were originally used for vascular malformations, are readily absorbed by melanin and haemoglobin. Additionally, the pulse duration is much longer than that of Q-switched pigment-specific lasers. PDLs may have stronger photothermolytic effects on surrounding naevus cells not containing melanin, thereby reducing the number of naevus cells. Another possibility is that the decreased microvascular supply negatively influences the viability of naevus cells. Some authors have demonstrated the presence of residual naevus cells deep in the dermis, even after multiple rounds of pigment-specific laser treatment, 4,5,24 indicating that the microscopic scar in the upper dermis masks underlying residual naevus cells. 24 In our study, the histological results from the patient who underwent 20 rounds of treatment showed that repeated laser treatment reduced the number of naevus cells. No residual naevus cell was detected in any layer of the skin after the 16th round of treatment (Fig. 8). In this case, skin atrophy and changes in skin texture were observed macroscopically and microscopically after laser treatment. The decreased dermal thickness may improve penetration of the laser beam to the deeper dermis. This study shows that combined PDL and QsRL treatment may reduce the number of naevus cells, including those deep in the dermis. If the risk of malignant change is shown to be attributable to the sheer number of melanocytes, 9 our treatment method could reduce this risk. All patients started therapy at 26 months (4 26 months, average 16Æ1 months) after birth. We believe that the initiation of laser treatment as early as possible provides the best results and reduces the amount of treatment required. Dave and Mahaffey 7 reported three cases showing good results after early combined laser treatment with CO 2 and Nd:YAG lasers.

6 1090 Combined pulsed dye and Qs-ruby laser treatment for CMN, E. Funayama et al. (c) (d) (e) Fig 8. (a e) Histological findings in the skin lesion specimens from case 3. At 3 months after the seventh round of treatment, many naevus cells were present in the papillary and reticular dermis (a, d). At 3 months after the 14th round of treatment, naevus cells were found in the deep reticular dermis. At 3 months after the 16th round of treatment, no residual naevus cells or amorphous fibrosis were found in any skin layer (c, e). A large number of keratinocytes containing melanin granules were present in the basal layer of the epidermis (c). Atrophic changes of the skin were found in (c) compared with. Haematoxylin and eosin staining. Kishi et al. 4 emphasized the efficacy of early serial QsRL treatment for CMN, because naevus nests tend to reside superficially in infants, and infant skin is more transparent. Nodule lesions in large CMN should be excised because nodules arising from within large CMN probably exhibit atypical features that distinguish them from melanomas. Approximately 60% of all melanomas occurring during the first decade of life arise from large CMN. 25 Short- and longterm monitoring for the two complications that cause most concern malignant melanoma and neurocutaneous melanosis 1 is needed during and after laser therapy. Long-term follow-up for monitoring both any recurrence of pigmentation and the development of malignant neoplasms will continue. Any disturbing findings in the patients presented here during follow-up will be reported because this is a new treatment technique for CMN. In conclusion, combined PDL and QsRL treatment results in far less scarring and disfigurement than excision and grafting, and greatly improves cosmetic appearance. It also produces a remarkable reduction in the number of melanocytic naevus cells, and may reduce the risk of melanoma development. It will almost certainly be of benefit in the psychological and social development of affected children. What s already known about this topic? Large congenital melanocytic naevi (CMN) have been treated with ablative and pigment-specific lasers besides surgical excision. Combination lasers may be useful in the treatment of CMN. What does this study add? Pulsed dye laser (PDL) which is commonly used for vascular lesions can remove naevus cells in CMN without severe scarring and disfiguring appearance. Combined PDL and Q-switched ruby laser treatment is effective for large to giant CMN. References 1 Arneja JS, Gosain AK. Giant congenital melanocytic nevi. Plast Reconstr Surg 2009; 124:1 13e.

7 Combined pulsed dye and Qs-ruby laser treatment for CMN, E. Funayama et al Horner BM, El-Muttardi NS, Mayou BJ. Treatment of congenital melanocytic naevi with CO 2 laser. Ann Plast Surg 2005; 55: Kono T, Erçöçen AR, Chan HH et al. Effectiveness of the normalmode ruby laser and the combined (normal-mode plus Q- switched) ruby laser in the treatment of congenital melanocytic nevi: a comparative study. Ann Plast Surg 2002; 49: Kishi K, Okabe R, Ninomiya E et al. Early serial Q-switched ruby laser therapy for medium-sized to giant congenital melanocytic naevi. Br J Dermatol 2009; 161: Kono T, Erçöçen AR, Nozaki M. Treatment of congenital melanocytic nevi using the combined (normal-mode plus Q-switched) ruby laser in Asians: clinical response in relation to histological type. Ann Plast Surg 2005; 54: Chong SJ, Jeong E, Park HJ et al. Treatment of congenital nevomelanocytic nevi with the CO 2 and Q-switched alexandrite lasers. Dermatol Surg 2005; 31: Dave R, Mahaffey PJ. Combined early treatment of congenital melanocytic naevus with carbon dioxide and Nd:Yag lasers. Br J Plast Surg 2004; 57: August PJ, Ferguson JE, Madan V. A study of the efficacy of carbon dioxide and pigment-specific lasers in the treatment of mediumsized congenital melanocytic naevi. Br J Dermatol 2011; 164: Reynolds N, Kenealy J, Mercer N. Carbon dioxide laser dermabrasion for giant congenital melanocytic nevi. Plast Reconstr Surg 2003; 111: Klimer SL, Lee MS, Grevelink JM et al. The Q-switched Nd:YAG laser effectively treats tatoos. A controlled, dose response study. Arch Dermatol 1993; 129: Kopf AW, Bart RS, Hennessey P. Congenital nevocytic nevi and malignant melanomas. J Am Acad Dermatol 1979; 1: Gar LM, Rivers JK, Kopf AW. Melanomas arising in large congenital nevocytic nevi: a prospective study. Pediatr Dermatol 1988; 5: Marghoob AA, Schoenbach SP, Kopf AW et al. Large congenital melanocytic nevi and the risk for the development of malignant melanomas. Arch Dermatol 1996; 132: DeDavid M, Orlow SJ, Provost N et al. A study of large congenital melanocytic nevi and associated malignant melanomas: review of cases in the New York University registry and the world literature. J Am Acad Dermatol 1997; 36: Quaba AA, Wallace AF. The incidence of malignant melanoma (0 to 15 years of age) arising in large congenital nevocellular nevi. Plast Reconstr Surg 1986; 78: Bittencout FV, Marghoob AA, Kopf AW et al. Large congenital melanocytic nevi and the risk for development of malignant melanoma and neurocutaneous melanocytosis. Pediatrics 2000; 106: Marghoob AA, Agero AG, Benvenuto-Andrade C et al. Large congenital melanocytic nevi, risk of cutaneous melanoma, and prophylactic surgery. J Am Acad Dermatol 2006; 54:868 70; discussion Streams BN, Lio PA, Mihm MC et al. A nonepidermal, primary malignant melanoma arising in a giant congenital melanocytic nevus 40 years after partial surgical removal. J Am Acad Dermatol 2004; 50: Rhodes AR, Wood WC, Sober AJ et al. Nonepidermal origin of malignant melanoma associated with a giant congenital nevocellular nevus. Plast Reconstr Surg 1981; 67: Dellon AL, Edelson RL, Chretien PB. Defining the malignant potential of the giant pigmented nevus. Plast Reconstr Surg 1976; 57: Arons MS, Hurwitz S. Congenital nevocellular nevus: a review of the treatment controversy and a report of 46 cases. Plast Reconstr Surg 1983; 72: Ferguson RE Jr, Vasconez HC. Laser treatment of congenital nevi. J Craniofac Surg 2005; 16: Hafner C, Stempfl T, Bäumler W et al. Gene expression profiling of melanocytes following Q-switched ruby laser irradiation. Dermatology 2008; 216: Imayama S, Ueda S. Long- and short-term histological observations of congenital nevi treated with the normal-mode ruby laser. Arch Dermatol 1999; 135: Kaplan EN. The risk of malignancy in large congenital nevi. Plast Reconstr Surg 1974; 53:421 8.

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