Treatment of Ota’s nevus by Q-switched alexandrite laser : therapeutic outcome in relation to clinical and histopathological findings

ARTICLE

Ota's nevus is a dermal melanocytic disease presenting as mottled, blue or brown partially confluent macules occurring in the sclera and the surrounding skin innervated by the first and second branches of the trigeminal nerve. It is more common in Asians (0.6% of all dermatology outpatients in Korea [1] and 0.2-0.8% in Japan [2]) than in Caucasians. Various treatment modalities including surgical removal and skin grafting, dermabrasion, and electrodessication have been associated with scarring. Dry ice application may be effective but great precision is required to avoid scar formation. Since the introduction of the selective photothermolysis [3] concept, Q-switched ruby lasers (694 nm, 30-40 nsec) [4-6] have been used to selectively destroy the melanosomes in the nevus cells while sparing the surrounding structures. The advantage of selective photothermolysis is that it removes deep seated pigments without scar formation.

Recently, Q-switched alexandrite laser (755 nm, 100 nsec) has been shown to interact selectively with the melanosome [7, 8]. We evaluated the clinical efficacy of the Q-switched alexandrite laser in relation to the histopathological findings.

Materials and methods

Patients

Fifty-five Korean patients (39 female and 16 male), aged 3-56 (mean, 25 years), with Ota's nevus were included in the study. The patients were consecutively included from September 1994 to September 1995. All patients signed informed consent forms after thorough explanation of the protocol, which was approved by the institutional review board of Ajou University Hospital.

Laser

We used a Q-switched alexandrite laser specified with 100 nsec pulse length, emitting at 755 nm and with a 3 mm diameter spot-size (Tattoo laser^®, Candela Laser Co., model.TL-1). The lesional skin was irradiated with fluences of 7.5 J/ cm². The treatment intervals were three months. In each of the three sessions, the entire affected area was treated at an energy density of 7.5 J/cm². Topical anesthetics (EMLA^® cream; a mixture consisting of lidocaine 5% and prilocaine 5% ), local infiltration of 2% lidocaine hydrochloride or oral analgesic was given before laser treatment. Response to therapy was evaluated through independent observation and rating of sequential photographs by two physicians, Dr. Won Hyoung Kang and Dr. Eun-So Lee.

Histopathological studies

Two mm punch biopsies were taken from all patients before laser exposure. Biopsy sites were chosen carefully to represent the whole lesion in terms of the color. For most patients the color was homogeneous except for slight regional accentuation or fading. From selected patients, we took the punch biopsy immediately after laser exposure, 14 days after and 15 months after. Then the specimens were routinely processed for light microscopy. Briefly, tissue specimens were fixed in 4% buffered formaldehyde, embedded in paraffin, sectioned, and stained with hematoxylin and eosin for light microscope examination. All specimens were evaluated by a micrometer on the eyepiece of a microscope for the depths of dermal melanocytes. The depths were assessed by measuring from the top of the granular cell layer of epidermis. Sections were reviewed by two dermatologists. Serial sections were made to assure the maximal depth of the nevus.

Clinical evaluation

All patients were photographed before each treatment session and 6 months after the last therapy. All films were processed by the same laboratory. A clinical grading system was used for the evaluation [9]. Two physicians (ES Lee and WH Kang) independently rated the clinical improvement as follows; poor (grade 1, disappearance of 0-25% of pigments or presence of scarring or recurrences), fair (grade 2, 25-50%), good (grade 3, 50-75%) or excellent (grade 4, 75-100%)

Statistical analysis

Statistical analysis was performed using student t-test, analysis of variance, and Chi square test.

Results

Clinical findings

The color of the lesions, before treatment, was blue black in 36 patients (65%), dark brown in 13 (24%) and light brown in 6 (11%). Among the 55 patients treated with the Q-switched alexandrite laser, the therapeutic effect for 27 patients (49%) was excellent; for 17 (31%) was good, for 7 (13%) was fair, and for 4 (7%) was poor. Figs 1 and 2 show examples of excellent results. The patients received three sessions of laser treatment, covering the entire lesion each time. Most patients developed urticaria-like swellings immediately after irradiation (7.5 J/cm²), which lasted 30-60 min. Topical anesthetics or oral analgesic could lessen the pain, but complete analgesia was obtained only after local procain infiltration. Periorbital lesions were extremely pain sensitive upon laser irradiations, where we used local anesthesia.

Side effects. Temporary side effects included erythema, urticarial wheal, periorbital edema, vesicle, and crust, which were spontaneously reversed in the first hour or after several days. Postinflammatory hyperpigmentation developed in 30 patients (55%) within 2 weeks after treatment, disappearing within 4 months with or without depigmenting agents (4% hydroquinone and/or 0.025% retinoic acid) (Fig. 3). The hyperpigmentation tended to be higher for dark skin (p = 0.038) : 3/10 (30%) in skin type III, 13/25 (52%) in skin type IV and 14/20 (70%) in skin type V (Chi square test, p = 0.037). But, there were no serious complications such as infection, scarring or textural change.

Histopathological findings

Selective destruction of melanocytes. The pathological changes immediately after (within 5 min) laser therapy showed selective injury to the epidermal and dermal melanocytes and scattered melanosomes throughout the dermis (Fig. 4). In addition, epidermal keratinocytes showed mild vacuolar changes. Biopsy specimens taken 14 days after the first irradiation revealed a regenerated epidermis, with slightly increased epidermal melanin. There was mild perivascular inflammatory infiltration and non-repopulating dermal melanocytes. Fifteen months after the first irradiation, there were no signs of repopulating dermal melanocytes but a few melanophages were seen in the perivascular area. No evidence of fibrosis was seen.

Depth of dermal melanocytes. Biopsies taken on the representative sites for color, before laser treatment showed depths of 1.3 ± 0.1 mm (mean ± SE, n = 55), ranging from 0.3-3.5 mm. Six patients (11%) showed a depth of 0.5 mm or less, 15 patients (28%) showed 0.5-0.99 mm, 19 patients (36%) showed 1-1.49 mm, 11 patients (21%) showed 1.5-1.99 mm and 2 patients (4%) showed depths beyond 2 mm. Ota's nevus with a blue black color showed deeper infiltration of melanocytes into the dermis (1.44 ± 0.1 mm) than the dark brown nevus (1.05 ± 0.1 mm) (p = 0.034, Fig. 5a). The light brown nevus (1.10 ± 0.2 mm) had a smaller depth than the blue black nevus, however it was not significant (p = 0.19).

Clearing vs depth. Patients with excellent results showed shallower depth (1.10 ± 0.1 mm) of melanocyte than patients with poor (1.70 ± 0.2 mm) or fair (1.50 ± 0.1 mm) results (mean ± SE, p = 0.048, p = 0.030, respectively; Fig. 5b). The excellent group showed shallower depth than the good group (1.48 ± 0.2 mm), however it was not statistically significant (p = 0.058). Nevus with a depth of 1 mm or less (35%, 19/55) showed good (grade 3) or excellent results (grade 4), while deeper lesions showed variable results from grade 1-4 (Fig. 5b). Color of the nevus (blue black, dark brown or light brown) did not affect the outcome, p > 0.05 (Fig. 5c). Therefore color itself is not a reliable indicator for predicting therapeutic outcome.

Discussion

Efficiency of Q-switched alexandrite laser. Our study confirmed that the Q-switched alexandrite laser is a very effective and safe tool for treating Ota's nevus. We observed no serious complications such as scarring or textural changes but reversible side effects such as transient urticaria-like swelling or postirradiation hyperpigmentation (52% in skin type IV, 70% in V). After treatment with the Q-switched alexandrite laser, 49% (27/55) of the patients had excellent results in which more than 75% of the pigments cleared, and 31% (17/55) showed good results, which is comparable to the results of Alster & Williams [7] (50% lightening in average, 4.75-7.0 J/cm², three treatments, n = 7 patients).

Geronemus [10] (1992) reported good effects with the Q-switched ruby laser. Among 15 patients, 4 (27%) obtained complete clearing and the remaining 11 (73%) showed more than 50% lightening. Since then, less dramatic results have been reported with Q-switched ruby lasers (Lowe et al. [11], 1993, excellent-good 80%, n = 16; Chang et al. [12], 1996, excellent 45%, good 23%, n = 47; Shimbashi et al. [13], 1996, excellent 33%, good 50%, n = 24; Yang et al. [6], 1996, excellent-good 80%, n = 80), which are similar to our present data (excellent 49%, good 31%, n = 55). Watanabe et al. [5] (1994) reported better results (excellent 13%, good 84%, n = 31).

Biopsy specimens taken immediately after irradiation showed findings (Fig. 4) consistent with selective photothermolysis [3] of melanosomes sparing the surrounding melanosome-free structures, which is possible because the laser pulse (100 nsec) is shorter than the thermal relaxation time of melanosome (500-1,000 nsec). Dermal melanocytes were the main target, but epidermal damage was not negligible (because of melanosomes in melanocytes and keratinocytes), developing clinically as hyperpigmentation after each treatment. Hyperpigmentation following Q-switched alexandrite laser treatment is a cause of cosmetic disability and psychological stress for the patients. So in some cases, it was necessary to delay laser treatment until the hyperpigmentation disappeared. For the patients with skin type IV or V, we explained in advance the possibility of hyperpigmentation following laser exposure. The nature of postirradiation hyperpigmentation is an increase in epidermal melanin contents (dermal pigments decreased), which was clarified by histopathological examinations. Epidermal injuries, ranging from mild vacuolar changes of the keratinocytes (Fig. 4) to total epidermal necrosis (not shown), were evident in immediate postirradiation skin samples. Injured epidermal keratinocytes may release various kinds of cytokines, which may stimulate melanocytes to produce more melanosomes.

Efficient irradiation schedule. After four years of experience with the Q-switched alexandrite laser, we are now doing 3 month intervals for the first year, 6 month intervals for the second year and 12 month intervals thereafter. We prefer to irradiate the entire lesion at each treatment to shorten the total treatment period and to shorten the post-irradiation hyperpigmentation periods which usually last 2-3 months and often cause great psychological stress to the patient. The other reason for this relatively long interval (compared to the 3 month intervals previously used) is to give enough time for the irradiated skin to clear up the disintegrated melanosomes by tissue macrophages [8]. The patient with dark skin (type IV and V) should be told, before starting on the Q-switched alexandrite laser treatment, that there might be no apparent clearing of the pigment for the first 6-12 months of treatment.

Is color of the nevus a reliable indicator of therapeutic outcome? Frequently the patients want to hear about the results before starting treatment so that they can decide whether to receive Q-switched alexandrite laser treatment or not. Unfortunately there are no exact indicators for predicting therapeutic outcome. Color of the lesion did not affect the outcome (Fig. 5c). However, depth of the lesion was significantly related to the outcome. Patients with excellent results showed shallower depth than poor or fair results (1.1mm vs 1.7 or 1.5 mm; mean values respectively). In addition nevus with a depth of 1 mm or less (35%, 19/55) showed good or excellent results. Although the blue black nevus showed a tendency for deeper infiltration of melanocytes than a light or dark brown nevus, there was no correlation between nevus color and melanocyte depth (Fig. 5a), nor between color and therapeutic outcomes (Fig. 5b). (There was no positive correlation between color of the nevus and pigment clearing.)

Patients' expectations for 100% clearing without scarring. Q-switched alexandrite laser is a very effective and safe tool for treating Ota's nevus. However the limitations include: 1) frequent development of postinflammatory hyperpigmentation especially for skin type IV and V, 2) delayed appearance of therapeutic effect, and 3) lack of 100% clearing. In our observations (not shown here), less than 10% of the treated patients showed 100% clearing within three years after beginning Q-switched alexandrite laser treatment. Patients' satisfaction levels were low in the first year of treatment, about one third admitted some improvement, which discourages continuation of the laser treatment. In the second or third year, many patients showed a moderate degree of satisfaction. The questions still remain: what percentage of patients will have complete clearing of Ota's nevus with Q-switched alexandrite laser and how long will it take? Although these questions may take years to answer, they require serious consideration because the patients are not satisfied with 80% or 90% clearing, but rather expect 100% clearing.

CONCLUSION

Acknowledgement

This study was supported by "98 Good Health with Search and Development Project (HMP-98-M-2-0021)" from Ministry of Health and Welfare, Republic of Korea to Won-H. Kang and Eun-So Lee.

We thank Young Bae Kim for preparation of the histopathologic slides and Heather Yu for her assistance in preparing the manuscript.

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