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Background Nevus of Ota is a benign bluish or gray-brown lesion of the eye and the surrounding skin that has been reported to occur in about 1 in 200 people in Japan. Prior treatments have either been ineffective or caused scarring. The Q-switched ruby laser can produce very short high-energy pulses and can selectively target cells that contain pigment, such as dermal melanocytes.
Methods We treated the skin lesions of 114 patients (25 male and 89 female) with nevi of Ota with a Q-switched ruby laser set to deliver pulses of 6 J per square centimeter of body-surface area at a wavelength of 694.3 nm, with a pulse duration of 30 nanoseconds. The interval between treatments ranged from three to four months. Five dermatologists who were not familiar with the patients independently compared a full set of pretreatment and post-treatment photographs of each patient and determined the percentage of pigment lightening of the affected areas using standard criteria.
Results Of the 35 patients who received four or five treatments, 33 had an excellent response (lightening of 70 percent or more), and 2 had a good response (lightening of 40 to 69 percent). Of the 31 patients who received three treatments, 4 had an excellent response, 26 a good response, and 1 a fair response (lightening of 10 to 39 percent). Of the 25 patients who received two treatments, 2 had an excellent response, 16 a good response, and 7 a fair response. Of the 23 patients who received one treatment, 3 had a good response, 13 a fair response, and 7 no response (lightening of 9 percent or less). No patient had hypertrophic or atrophic scarring; eight patients had postinflammatory hyperpigmentation for up to two months after the first treatment.
Conclusions Selective photothermolysis with the Q-switched ruby laser is a safe and effective method for lightening nevi of Ota. Multiple treatments increase the response rate.
Lasers have also been used to treat nevi of Ota in the past,3 but initially without a firm theoretical or experimental basis. Early treatment techniques were ineffective, and complications such as scarring were common. These disappointing results fostered the belief that laser therapy was harmful, despite the availability of a wide variety of techniques. Selective photothermolysis produces specific, heat-mediated injury to pigmented skin cells and other structures by means of brief and selectively absorbed laser pulses.4,5 Melanin, the pigment in melanosomes, is a potential target for selective photothermolysis, because it is the primary light-absorbing compound of cells exposed to laser energy of a certain wavelength.6
Recently, pulses of Q-switched ruby lasers have been shown to interact selectively with the cutaneous pigmentary system.7 In this technique, energy obtained from a deep-red wavelength (694.3 nm) is allowed to build up in the laser, creating powerful high-energy bursts. One of the benefits of the Q-switched ruby laser may be in the selective targeting of cells that contain pigment, such as dermal melanocytes. To evaluate this technique, we treated patients with nevi of Ota with very short pulses of laser energy conforming to the conditions for selective photothermolysis.
Methods
Laser
A Q-switched ruby laser (model LRT-301A/QS, Toshiba, Tokyo, Japan) was used to deliver pulses of 6 J per square centimeter of body-surface area at a wavelength of 694.3 nm; each pulse lasted 30 nanoseconds. The pulses were delivered through an articulated arm (an optical path that permits flexibility in delivery) and a square aperture (measuring 4 by 4 mm) in contact with the skin. The accuracy of the aim of the device was enhanced through the use of a helium-neon laser whose beam was delivered along the same optical path as the treatment beam. The pulse energy was measured with a meter (model DGX, Ophir, Jerusalem, Israel). The energy density of the laser beam was uniform across the aperture. The laser-pulse energy was typically reproducible from pulse to pulse within ±10 percent.
Patients
The study group comprised 114 patients (25 male and 89 female) with nevi of Ota, ranging in age from 8 to 63 years (mean [ ±SD], 30 ±11), who were treated at the Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan, between September 1990 and August 1993. Only patients for whom both pretreatment and post-treatment clinical photographs were available for comparison were studied. One patient was Korean; all the others were Japanese. Approval for the study was obtained from the institutional review board of Teikyo University. After the nature of the procedure was fully explained, written informed consent was obtained from all patients.
Technique
The patients were treated either without anesthesia or with topical anesthesia (5 percent lidocaine hydrochloride ointment). During all treatment sessions, the eyes of the patients and the clinical staff were protected. The treatment intervals ranged from three to four months. In most sessions, the entire affected area was treated at an energy density of 6 J per square centimeter.
Forty patients had punch biopsies (3 or 4 mm in diameter) of temporal lesions after receiving local anesthesia (subcutaneous injection of 1 percent lidocaine with epinephrine). This biopsy site was chosen because it can be easily hidden by hair. All 40 patients had only one biopsy; some were obtained before treatment, some immediately after treatment, and some at various later times. Histopathological examination was by light and electron microscopy.
Analysis
All patients were photographed before treatment and after each treatment session (every three to four months), including the final session of the study period. Whenever possible, photographs were taken with the same camera, magnification, lighting, angle, and film exposure. Five dermatologists who were not familiar with the patients independently compared the full set of images of the treated nevi with the pretreatment images using photographic slides obtained at each session. Before evaluating these images, the dermatologists agreed on a system of grading the lightening of bluish pigment, hypopigmentation, hyperpigmentation, and scarring based on an examination of several prototypical slides. The percentage of lightening of the nevi was determined by comparing them with normal skin. In this grading system, which used increments of 5 percent, a score of 100 percent corresponded to complete clearing, with no detectable differences from normal skin, and a score of 0 percent corresponded to no clearing. The independent ratings of the five dermatologists were averaged to determine the final degree of lightening. Five levels of treatment response were established according to the percentage of pigmentary lightening: excellent in cases with lightening of 70 percent or more, good in cases with lightening of 40 to 69 percent, fair in cases with lightening of 10 to 39 percent, no change in cases with lightening of 9 percent or less, and worse in cases with darkening of the nevi. The side effects of atrophy and scarring were graded as follows: 0 for no scar, 1 for epidermal alteration, 2 for sclerosis, and 3 or more for hypertrophic scarring. Cutaneous depression and post-treatment hyperpigmentation and hypopigmentation were documented as either present or absent.
Results
Clinical Course
A white square appeared immediately after pigmented skin was exposed to the Q-switched ruby laser.7 A wheal-and-flare response was seen around the irradiated sites about five minutes later. This response was pronounced when periorbital areas were treated. The whitening was more intense in pigmented skin than in the surrounding skin. This white color faded within about 20 minutes.
Superficial punctate erosions limited to the pigmented area were seen in some patients immediately after laser treatment. Occasional petechiae, purpura, and rare punctate hemorrhages confined to the pigmented area were seen, especially in the periorbital areas in older patients with fragile blood vessels. Purpura and hemorrhages were not seen in nonpigmented areas. No patients had exudates or gross bleeding.
The wheal-and-flare response lasted for several hours, and erythema was seen for up to 24 hours. Periorbital edema sometimes persisted for two or three days. Vesicles were occasionally seen during the first three days after laser treatment followed by formation of a brown crust over the treated pigmented area during the first two weeks. After desquamation of the crust in three patients with brown macules, the tint of the nevi changed from brownish to bluish. The changes in the color of other lesions, however, were unremarkable. Eight patients had postinflammatory hyperpigmentation for up to two months after the first treatment; however, these patients did not have remarkable postinflammatory hyperpigmentation after the second treatment. Gradual lightening of the lesions was usually evident after two or three laser treatments. No postexposure infections or hypertrophic or atrophic scarring was noted.
Clinical Efficacy
The clinical results of laser treatment are summarized in Table 1. The efficacy rate (the percentage of patients with a good or excellent response to treatment) increased with the number of treatments. Among the 23 patients who had only one treatment, 3 had good responses, 13 had fair responses, and 7 had no response. In contrast, all 18 patients who had five treatments had excellent responses. Examples of the responses in three of the patients who had five treatments are shown in Figure 1, Figure 2, and Figure 3.
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Before treatment, elongated, slender, often slightly wavy dendritic cells containing melanin granules were scattered among the collagen bundles in skin-biopsy specimens. Electron microscopy revealed dermal melanocytes that contained numerous melanosomes. Basal lamina and lamina lucida surrounded some melanocytes. An extracellular sheath of varying thickness surrounded dermal melanocytes outside the basal lamina or the plasma membrane of the melanocytes (Figure 4A).
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On electron microscopy, the melanocytes were seen as cellular debris juxtaposed with altered melanosomes. Most melanocytes had complete disruption of melanosomes, characterized by irregular contours, enlargement, and marked disorganization of the internal structures (Figure 4B). These morphologic changes are similar to those described previously.7,8,9,10,11,12 The melanocytes in the papillary dermis were completely disrupted, making it very difficult to recognize the nuclei and cell membranes. Melanocytes in the reticular dermis, however, had less degeneration, with disruption ranging from pyknotic nuclei with clumped chromatin and giant intracytoplasmic vacuoles to internal disruption of nuclei with peripheral condensation of electron-dense chromatin and ruptured membrane-bound intracytoplasmic vacuoles that pushed the nuclei and damaged melanosomes to the periphery. The degenerative changes were less severe in melanocytes in deeper areas of the skin. No alterations were noted in cells without melanosomes or in collagen bundles, even in areas adjacent to those containing damaged melanocytes (Figure 4C).
The depth to which melanocytes were destroyed was measured in six biopsy specimens of temporal skin obtained within one day after laser treatment. Degeneration of melanocytes was seen to a depth of 1.5 mm from the skin surface, which is nearly equivalent to the thickness of the epidermis and the dermis in the temporal area (1.6 mm).
There was a neutrophilic inflammatory response during the first few days after treatment. By day 10, most of the altered melanosomes were within the macrophages. Biopsy specimens obtained from areas of skin with an excellent response to the Q-switched ruby laser had a decreased number of melanocytes. No evidence of fibrosis was seen in any biopsy specimen.
Discussion
Dermal tissue in nevi of Ota contains large amounts of melanin, which provides an excellent target for the laser. Electron-microscopical examination of nevi immediately after exposure showed destruction of dermal melanocytes, but no changes in surrounding tissues. Skin-biopsy specimens obtained after healing showed a completely normal papillary dermis with some nevus cells remaining deep in the dermis. The absence of fibrosis in the specimens is consistent with the absence of clinical scarring in these patients. The Q-switched ruby laser appears to cause selective destruction of pigmented cells, with negligible damage to surrounding tissues.
Histologic examination showed degeneration of melanocytes to a depth of 1.5 mm from the skin surface, which is about the thickness of the temporal epidermis and dermis. This suggests that pigment macules at the temple can be almost completely eliminated with repeated laser treatments.
Prior studies of the Q-switched ruby laser in the treatment of nevi of Ota13,14,15,16 included small numbers of patients, and the number and frequency of treatments varied. We followed a large number of patients with nevi of Ota for a relatively long time and used a standard approach to therapy. Lightening of the pigmented areas of nevi was seen in all patients, although it was not apparent immediately after laser treatment.
Most patients who had had only one or two sessions by August 1993 and had had no response or only a fair response to laser treatment wanted further treatments. We continued to treat these patients in the manner described in the study. All these patients had continued lightening of the affected areas, with no side effects (data not shown). No reversion to the original color has been seen up to three years after the last laser treatment.
The energy density we used was lower than that reported by others,13,14,15 because despite differences in the intensity of the pulse, the threshold exposure for melanosomal injury remains essentially the same as long as the pulse width (the duration of exposure to the laser) is shorter than the estimated thermal relaxation time of melanosomes (the time needed for 50 percent of the incident energy to dissipate from the target in the form of heat).17
The Q-switched ruby laser is also useful in removing tattoos, in particular those with blue-black pigment. Tattoos applied by amateur tattooers respond better than those applied by professional tattooers,18 because the latter contain a variety of metals in addition to organic dyes. Tattoos applied by professionals may be thermally and mechanically more stable than those applied by amateurs, which often contain amorphous carbon or graphite.
When the Q-switched ruby laser was used to treat tattoos applied by amateurs, marked lightening was seen immediately after desquamation of the crusts covering the treated areas.18 The process of lightening such tattoos differs from the process of lightening nevi of Ota, although both involve pigments located in the dermis. Laser pulses are absorbed by melanin in nevi of Ota and by amorphous carbon or graphite in tattoos. Melanin is thermally so stable that it remains in the exposed areas even after laser pulses have destroyed dermal melanocytes. The nevi of Ota lighten only after the melanin within the altered melanosomes has been phagocytosed by macrophages, which are attracted by the inflammatory reaction, and removed to lymph nodes or other sites. In laser-treated patients with nevi of Ota, it is therefore possible that melanin-laden macrophages that have migrated to lymph nodes may remain there and that melanin may gradually accumulate in regional lymph nodes. In most tattoos applied by amateurs, macrophages have already phagocytosed amorphous carbon or graphite, so laser pulses destroy the heat-labile tattoo pigments, as well as the macrophages containing them. Thus, these tattoos may lighten quickly.
In conclusion, selective photothermolysis with the Q-switched ruby laser is a safe and effective method for lightening nevi of Ota. Multiple treatments increase the response rate. We do not know whether the interval between laser treatments or the number of treatments is more important in lightening the pigmentation. The treatment interval may be more important, because clinical improvement was noted six months to one year after the last treatment in some patients (not included in this study) who received only one or two treatments. Moreover, not all of the melanin within the melanosomes damaged by laser irradiation is transported to lymph nodes. Thus, additional treatments may be required.
Supported in part by funds from the Cosmetology Research Foundation (J 90-11) and by a grant from the Ministry of Education, Science, and Culture of Japan (04670649).
We are indebted to Drs. Mayumi Tosa, Atsuko Gotoh, Chikako Matsumura, Hiromi Suenaga, and Chitose Takahashi for their photographic analysis and to the Toshiba Corporation for providing technical assistance and the Q-switched ruby laser.
Source Information
From the Department of Dermatology, Teikyo University School of Medicine, 11-1, Kaga, 2 chome, Itabashi-ku, Tokyo 173, Japan, where reprint requests should be addressed to Dr. Watanabe.
References
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