1. Harvard Dermatology Program, Boston, USA
2. Division of Dermatology, Department of Medicine, the University of Hong Kong
and Chinese University of Hong Kong, Hong Kong SAR

ABSTRACT

The development of selective photothermolysis has enabled removal of targets such as melanin. Both lasers and intense pulsed light (IPL) sources have been used in the treatment of pigmented lesions, however careful selection is important to ensure success. This is especially true in darker skinned individuals where the risk of postinflammatory hyperpigmentation (PIH) is high. The advent of the Q-switched laser, IPL, and now fractional photothermolysis (Fraxel®, Reliant Technologies) offers a variety of ways to treat epidermal and dermal pigmentary disorders.

Key Words:
laser, intense pulsed light, Q-switched laser, fractional photothermolysis, pigmentary disorder, postinflammatory hyperpigmentation

In darker skinned individuals photodamage more commonly presents as pigmentary changes rather than wrinkling. This difference is partially due to the higher epidermal melanin content, which can predispose these patients to a higher risk for hyperpigmentation from light source treatment. Although several of these pigmented lesions are common among all skin types, we will focus on the parameters associated with Asian skin.

Epidermal Lesions

Lentigines

Lentigines are common in individuals from sun-exposed sites, and histologically demonstrate melanocyte proliferation without nest formation along the basement membrane. Q-switched (QS) lasers deliver short bursts of wavelength-specific energy that can be absorbed by melanocytes, i.e., QS Nd:YAG lasers (532nm or 1064nm), the QS alexandrite laser (755nm), and the QS ruby laser (694nm). The risk of postinflammatory hyperpigmentation (PIH) in the Asian population is estimated to be about 10%–25% with QS lasers, which have the advantage of achieving significant clearing even after one treatment session and are particularly effective for lightly pigmented lentigines. We routinely test spot, to minimize the risk of PIH. Another approach to removing lentigines is to use longer pulsed lasers in the microsecond domain that match the thermal relaxation time of the epidermis, thus confining the thermal injury to the epidermis.

Without the photomechanical effect associated with the use of QS laser, the risk of PIH associated with long pulsed laser is lower. For example, we use a long pulse 532nm Nd:YAG laser (2ms pulse duration, 6.5J/cm2 fluence, 2mm spot size without cooling or 12 J/cm2 with cooling sapphire window).

Recently, traditional vascular lasers have been employed to remove lentigines. Long pulsed dye laser (LPDL) (595nm) targets both hemoglobin and melanin. Compressing the skin surface during treatment and emptying the blood vessel minimizes damage of the vessels that can lead to bruising and subsequent PIH. A recent study in the treatment of lentigines in Asians, compared the use of LPDL (595nm) (fluence of 10–13J/cm2, pulse duration of 1.5ms) attached with a compression window vs. a QS ruby laser (694nm) (fluence of 6–7J/cm2, pulse duration of 30ns). The LPDL with compression window arm demonstrated superior results and fewer adverse effects.¹

Intense pulsed light (IPL) sources that emit a broad band of visible light (400–1,200nm) from a noncoherent filtered flashlamp, affects pigmentation via photothermal effects. IPL has been studied for the treatment of lentigines and ephelides with cutoff filters ranging from 550–590nm, a fluence of 25–35J/cm2, and a pulse width of 4.0ms.2 These studies have been performed on Asian skin with surprisingly no PIH. This lower risk of PIH and the limited postoperative downtime have made IPL a popular choice. The patient should understand, however, that multiple treatments may be necessary. In our practice, for those who do not wish to have any downtime, or for those who wish to improve not only their pigmentation, but also pore size and skin texture, we offer IPL treatment combined with other laser modalities in the same treatment session to obtain a better outcome.

Café au Lait Macules

Café au lait macules are seen at birth and may increase in size over time. Although multiple lesions are associated with neurofibromatosis, café au lait macules are a common finding at birth. They do not signify an increased risk of melanoma and can be removed for cosmetic reasons.

The use of Q-switched lasers in the treatment of café au lait patches has yielded variable results with a high risk of recurrence if pigment is left behind. There have also been reported incidences of paradoxical darkening. Comparison of frequency-doubled QS neodymium:YAG laser (532nm; spot size 2.0mm) and the QS ruby laser (694nm; spot size, 5.0mm) at a fluence of 6.0J/cm2 demonstrated variable responses. Our current approach is to use a long pulsed pigment laser to remove not only the epidermal melanocytes but also the hair follicle melanocytes. Our experience suggests a lower risk of recurrence (~40%) (See Figure 1).

Figure 1: Left: Café au Lait patch prior to treatment, cross-polarized photo.

Right: After 9 treatments with long pulsed alexandrite (755nm, 30–50 J/cm2, 10mm spot size, 3ms pulse width) every 6 weeks, cross-polarized photo.

Becker’s Nevus

Becker’s nevus, or pigmented hair epidermal nevus, is an uncommon hamartoma that can represent significant cosmetic concern. Histologically, there may be greater pigmentation in the basal region, increased melanophages, and large numbers of irregular, enlarged, smooth muscle fibers in the dermis. In the past, nonspecific treatments such as an argon or CO2 laser were used with associated scarring or permanent hypopigmentation.

We employ long pulse alexandrite 755nm (30–50J/cm2, 10mm spot size, 1.5ms) to target the pigment and surrounding hair follicle. We inform the patients of an approximately 50% success rate after four to eight treatment sessions. Scarring and hypopigmentation are possible side-effects. Other cases report superiority of the erbium:YAG laser 2940nm (28J/cm2, 3mm spot size) as compared to the QS 1064nm Nd:YAG laser (10J/cm2, 10ns pulse width, 3mm spot size).³ In a study of 22 patients treated with one pass mode erbium:YAG laser at 2-year follow-up, 54% achieved complete clearance while >50% improvement was noted by 100% of the patients.³ Slow repigmentation takes place over years but patients should be aware of potential mild permanent hypopigmentation (See Figure 2).

Figure 2: Left: A) Becker’s nevus on right forearm prior to treatment with diffuse hyperpigmentation and hypertrichosis.

Right: After 8 treatments with long pulsed alexandrite (755nm, 20–30 J/cm2, 10mm spot size, 3ms, pulse width) Note hypopigmentation and mild scarring with loss of hair. Kenacort and 5-FU injections were supplemented to minimize scarring.

Tips for Laser Treatment of Epidermal Pigmentation:

• Sun avoidance and/or pretreatment with chemical suppressants of melanin production such as 4% hydroquinone is important before and after the treatment.
• Test spots should always be done for QS lasers to reduce the risk of PIH.
• For long pulsed lasers, patients should be warned that several treatments will be necessary to achieve a significant degree of improvement, but there is less downtime and lower risk of PIH.
• Becker’s nevi can be removed with pigment removing lasers, but there is a risk of recurrence. It is to be further determined whether combination with ablative lasers will have a lower risk of recurrence.

Dermal or Mixed Lesions

Nevus of Ota/Hori’s Nevus

Two forms of primarily dermal pigmentation commonly seen in Asian patients include:

1) Nevus of Ota appears as slate blue pigmentation in a unilateral trigeminal nerve distribution emerging at birth or in young adulthood.

2) Hori’s nevus, also known as acquired bilateral nevus of Ota-like macules (ABNOM), or acquired dermal melanocytosis (ADM), presents as bilateral facial bluish-gray macules. Seen in 0.8% of the Asian population, Hori’s nevus typically affects the malar region, but the lateral temples, alae nasi, eyelids, and forehead can also be involved. Unlike nevus of Ota, the pigmentation in Hori’s nevus is acquired and does not involve the mucosa. Not uncommonly, melasma and Hori’s nevus can present concurrently.

The treatments for both types of dermal pigmentation are similar and again include the QS lasers. QS ruby (694nm), QS Alexandrite (755nm), and QS 1064nm Nd:YAG have all been used for the treatment of nevus of Ota with excellent results and similar minimal risk of complications. In our retrospective study of 46 children and 107 adults, >75% achieved a complete response with Q-switched ruby (694nm wavelength, 30ns pulse duration, 4mm spot size, 5–7J/cm2 fluence at 3–4-month intervals). Treatment is optimal at a younger age, as there is a lower number of mean treatments and lower rate of complications.⁴

Compared to nevus of Ota, Hori’s nevus is particularly challenging to treat and there are at least two potential reasons for this: 1) melanocytes are located perivascularly leading to a higher likelihood of PIH after laser therapy, and 2) there is a frequent association with melasma and thus, the associated presence of epidermal pigmentation. As such, combination approaches are frequently used.

Recently, the concurrent use of QS 532nm Nd:YAG in combination with the QS 1064nm Nd:YAG laser in a small study was shown to be more effective in reducing the degree of pigmentation of Hori’s nevus.5 Other employed techniques include the use of topical bleaching agents such as 0.1% tretinoin aqueous gel and 5% hydroquinone ointment containing 7% lactic acid to discharge epidermal melanin 4–6 weeks prior to treatment. PIH was documented in 10.5% of these cases as opposed to 50%–73% of patients in prior studies.6 We also treat our patients with both preoperative and postoperative topical bleaching agents.

The main issue for patients with Hori’s nevus is the downtime associated with frequent use of QS lasers. We are currently investigating the use of contact cooling together with a pulsed light source at the red light region (690–1000nm). The aim of this treatment is to achieve removal of these lesions by inducing apoptosis of the melanocytes after repeat treatments, and to reduce downtime.

Melasma

Melasma is a common yet difficult to treat pigmentary disorder, typically found symmetrically on the face of women. Risk factors include sun exposure, increased hormones, genetic predisposition, and phototoxic medications. While topical agents remain the first-line treatment for epidermal and mixed type of melasma, a laser or light source has been used for the more refractory lesions.

IPL theoretically offers an attractive alternative with minimal downtime, but may not be an effective, long-term treatment as a solo agent. IPL, used at 570nm and 590–615nm filters in 4-week intervals for a total of four treatments, was tested on Asian patients. There was a 39.8% improvement of the relative melanin index in the treatment groups compared with 11.6% improvement in the control group at week 16. There was however, repigmentation at the end of the 36-week treatment suggesting that maintenance therapy may be necessary.⁷ Patient expectations should include microcrust formation 2–3 days after irradiation with resolution within 1–2 weeks. QS 1064nm Nd:YAG laser (6mm spot size, 1.6J/cm2) can also be used for the treatment of melasma. Mild erythema can be used as the clinical endpoint and patients will require monthly treatment. The newest addition to the armamentarium is fractional photothermolysis (FP) (Fraxel^®, Reliant Technologies). FP involves the use of an infrared laser (1450nm or 1540nm) to create microcolumns of thermal injury surrounded by uninjured tissue. The columns of thermal injury surrounded by uninjured tissue are called microscopic treatment zones (MTZs). The density of MTZs can be varied for a given energy level. Reported side-effects are sunburn-like erythema that lasts 1–3 days. The original proof of principle study by Tannous, et al. demonstrated a marked reduction in both epidermal and dermal pigmentation 6 months after two full face FP treatments spaced 3 weeks apart.⁸ In a 10 patient study (Fitzpatrick skin types III-V) with 6–12mJ/MTZ and 2,000–3,500MTZ/cm2 for 4–6 treatments, 60% of the patients had 75%–100% clearing. Only 1/10 patients had PIH.⁹

We recently published an abstract on a study of 16 Asian patients using a lower dose of 125MTZ/cm2 at energy of 8mJ, every 2–4 weeks. Lower energy and density reduced pain and downtime. High density is not significantly effective and has a risk of hyperpigmentation in this skin-type population. The selective MTZs created by FP have been studied histologically. Microscopic epidermal necrotic debris (MENDs) forms by day 1 and is shed with the epidermis within 7 days. MENDs has been shown to contain melanin pigment and may serve as a “melanin shuttle”, which is rapidly eliminated by the keratinocyte migration from the borders of the MTZs. Furthermore, there is decreased melanin content in the basal cell layer after treatment. There was no reported relapse in melanin pigment at 3 months.¹⁰

Tips for Laser Treatment of Dermal and Mixed Pigmentation:

• A Wood’s lamp is helpful in determining the degree of epidermal and dermal components. Cross-polarizing magnification can help distinguish the 2 components during treatment.
• Reducing epidermal pigmentation with topicals or normal pulse laser may allow for deeper penetration of pigment lasers.
• Before and after photography is essential to help the patient appreciate improvement.

Conclusions

• Epidermal pigmentation is effectively targeted with Q-switched lasers. Pretreatment with melanin-inhibitory substances, longer pulse duration, and compression of vessels can help reduce the risk of PIH.
• IPL is an effective method of removing epidermal pigmentation with reduced downtime, but may require multiple treatments.
• Dermal pigmentation may be best treated with a combination of lasers such as Q-switched 532nm Nd:YAG in combination with the 1064nm laser.
• FP is an effective treatment of melasma and reduced density is important in the Asian skin type to reduce the risk of PIH.

References

1. Kono T, Manstein D, Chan HH, et al. QS Ruby versus long-pulsed dye laser delivered with compression for treatment of facial lentigines in Asians. Lasers Surg Med 38(2):94-7 (2005 Nov).
2. Kawada A, Shiraishi H, Asai M, et al. Clinical improvement of solar lentigines and ephelides with an intense pulsed light source. Dermatol Surg 28(6):504-8 (2002 Jun).
3. Trelles MA, Allones I, Moreno-Arias GA, et al. Becker’s naevus: a comparative study between erbium: YAG and Q-switched neodymium:YAG; clinical and histopathological findings. Br J Dermatol 152(2):308-13 (2005 Feb).
4. Kono T, Chan HH, Ercocen AR, et al. Use of Q-switched ruby laser in the treatment of nevus of Ota in different age groups. Lasers Surg Med 32(5): 391-5 (2003 May).
5. Ee HL, Goh CL, Khoo LS, et al. Treatment of acquired bilateral nevus of ota-like macules (Hori’s nevus) with a combination of the 532nm Q-Switched Nd:YAG laser followed by the 1,064nm Q-switched Nd:YAG is more effective: prospective study. Dermatol Surg 32(1):34-40 (2006 Jan).
6. Momosawa A, Yoshimura K, Uchida G, et al. Combined therapy using Q-switched ruby laser and bleaching treatment with tretinoin and hydroquinone for acquired dermal melanocytosis. Dermatol Surg 29 (10): 1001-7 (2003 Oct).
7. Wang CC, Hui CY, Sue YM, et al. Intense pulsed light for the treatment of refractory melasma in Asian patients. Dermatol Surg 30 (9): 1196-200 (2004 Oct).
8. Tannous ZS and Astner S. Utilizing fractional resurfacing in the treatment of therapy-resistant melasma. J Cosmet Laser Ther 7(1): 39-43 (2005 Mar).
9. Rokhsar CK and Fitzpatrick RE. The treatment of melasma with fractional photothermolysis: a pilot study. Dermatol Surg 31 (12): 1645-50 (2005 Dec).
10. Laubach HJ, Tannous Z, Anderson RR, et al. Skin responses to fractional photothermolysis. Lasers Surg Med 38(2):142-9 (2006 Jan).

¹Division of Dermatology, Department of Medicine, the University of Hong Kong, China
²Department of Plastic and Reconstructive Surgery, Tokyo Women’s Medical University, Tokyo, Japan

ABSTRACT

Lasers and intense pulsed light sources are frequently used for the treatment of pigmented lesions, and the appropriate selection of devices for different lesions is vital to achieving satisfactory clinical outcomes. In dark-skinned patients, the risk of post-inflammatory hyperpigmentation is of particular importance. In general, long-pulse laser and intense pulsed light sources can be effective with a low risk of post-inflammatory hyperpigmentation (PIH) when used for the treatment of lentigines. However, for dermal pigmentation and tattoo, Q-switched lasers are effective, with a lower risk of complications. In the removal of melanocytic nevi, a combined approach with a long-pulse pigmented laser and a Q-switched laser is particularly applicable.

Key Words: pigmented lesions, hyperpigmentation, lasers, intense pulsed light sources

The cutaneous application of lasers and intense pulsed light sources for the treatment of pigmented lesions can be divided into the following categories:

• Tattoos
• Epidermal pigmentation such as lentigines and café au lait patches
• Dermal pigmentation such as nevus of Ota, acquired bilateral nevus of Ota, and melanocytic nevi

Tattoos

The use of lasers has been effective in the removal of some,  but not all, tattoos. Q-switched lasers have been found to be safe and effective in the treatment of tattoos. The response to laser treatment can vary greatly due to the wide range of tattoo ink. Previous in vitro quantitative chemical analysis of tattoo pigments found that the most common elements were aluminium, titanium, and carbon. Titanium overrepresentation was identified as the main reason for a poor response to laser treatment. Picosecond lasers were found to be more effective in achieving a greater degree of clearing. To improve the clinical outcome, more recent developments have included the external application of magnets to improve the removal of magnetite skin tattoos after Q-switched laser treatment, and the use of intradermal focusing of the Q-switched laser.^1,2 In terms of complications, tattoos can darken after laser treatment due to the reduction of ferric oxide to ferrous oxide. This can be rectified with repeated Q-switched laser treatment and the use of a resurfacing laser. Less common complications include the development of allergic dermatitis or even anaphylactic shock after the laser surgery. Such reactions are thought to occur due to the release of allergic pigment into the extracellular space after laser exposure.

Epidermal Lesions

Lentigines

Lasers have been used for the treatment of lentigines, and although this is often effective for light-skinned patients with limited complications, for dark-skinned patients with a higher epidermal melanin content it can be associated with complications such as hyperpigmentation. Two years ago, our group performed an in vivo study of 34 patients and compared a Q-switched 532nm Neodymium:Yttrium-Aluminum-Garnet (QS 532nm Nd:YAG) laser to a long-pulse 532nm Nd:YAG laser.³ We found that the long pulse 532nm Nd:YAG laser (2msec pulse duration, 6.5-8J/cm2 fluence, 2mm spot size, with slate gray appearance as the clinical end-point) can result in a lower risk of PIH when used in the treatment of lentigines in Asians.³ We created controversy when we suggested that the photomechanical effect of QS lasers might not be desirable when used in such treatment. Intense pulsed light sources (IPL), which emit a broad band of visible light from a non-coherent filtered flashlamp, produce only photothermal effects. Recent studies that investigated the use of IPL to remove lentigines in Asians confirmed their effectiveness.⁴ Interestingly, no case of PIH was observed in two independent studies.

These observations confirm our hypothesis that the photomechanical effect of Q-switched laser for the treatment of lentigines in Asians is not desirable. The main concern regarding the use of the long-pulse laser for the treatment of cutaneous pigmented lesions is the potential of thermal diffusion from the epidermis to the dermis, which increases the risk of scar formation. To prevent such an occurrence, the pulse duration should be shorter than the thermal relaxation time of the epidermis basal layer, which was estimated to be in the range of 1.6-2.8ms if the epidermal basal layer thickness was 20mm.

It is now our routine approach to test patients with a long pulse 532nm Nd:YAG laser (2ms pulse duration, 6.5J/cm2 fluence, 2mm spot size), and if they respond well, we offer them full treatment. Those who do not wish to have down time, or those who develop post-inflammatory hyperpigmentation after the test, are offered IPL treatment, which requires several more treatment sessions to achieve the desired clinical outcome.

Café au Lait Patch

The use of lasers in the treatment of the café au lait patch has yielded variable results, and although some early studies indicated complete removal without recurrence, such findings have not always been repeated. Previous studies showed that 510nm pulsed dye lasers and copper vapor lasers can be used successfully, with no recurrence, at least one year after treatment. These reports were confirmed by others. Grossman, et al. used a QS Ruby laser and a frequency double Q-switched Nd:YAG laser, and found that the degree of clearance varied across lesions.⁵ Moreover, the categorization of the patches into the two histological sub-types that they identified did not help to predict the extent of the clinical response. We looked at the use of normal-mode ruby laser (NMRL) and compared it to QS Ruby laser in the clearing of café au lait patches in 33 patients. Our preliminary data indicated that there was a lower risk of recurrence when the NMRL was used (42.4% of recurrence, as compared to 81.8% recrrence in those who were treated with QS Ruby laser) 3 months after a single treatment. By affecting the follicular melanocytes, the long-pulse laser may reduce the recurrence rate. Further histological study is necessary to confirm this hypothesis.

Dermal Lesions

Nevus of Ota

Q-switched Alexandrite (QS Alex), QS Ruby, and QS 1064nm Nd:YAG have been used for the treatment of nevus of Ota with excellent results and minimal risk of complications. The clinical efficacy of the QS Ruby was confirmed when Watanabe and Takahashi⁶ studied 114 nevus of Ota patients and found that a good-to-excellent degree of lightening was achieved after three or more treatment sessions. The side-effects were few, with transient hyperpigmentation after the first treatment being the most common. Studies comparing the use of QS Alex and QS Nd:YAG lasers found that most patients better tolerated the former. However, QS Nd:YAG laser appeared to be more effective than QS Alex in the lightening of nevus of Ota after three or more laser treatment sessions. In terms of complications, hypopigmentation was common, especially among those treated with QS Ruby. The original pigmentation could also recur in patients after complete laser-induced clearing, which is an important issue, especially for pediatric patients. The risk of such recurrence is estimated to be between 0.6% and 1.2%. However, the use of QS Ruby laser for the treatment of nevus of Ota in children can achieve an excellent result in fewer sessions and at a lower complication rate than later treatment.⁷ Hence, the advantages and disadvantages of treating nevus of Ota early in childhood should be thoroughly discussed with the patient’s relatives.

Acquired Bilateral Nevus of Ota-like Macules (ABNOM) or Hori’s Macules

Acquired bilateral nevus of Ota-like macules (ABNOM), or Hori’s macules, are a pigmentary disorder that is clinically characterized by speckled or confluent brownish-blue or slate gray pigmentation over the face, and histologically characterized by diffuse upper dermal melanocytosis. Unlike nevus of Ota, the pigmentation occurs in a symmetrical bilateral fashion, has a late onset in adulthood, and does not involve the mucosa.

One hundred forty patients with ABNOM were treated with a Q-switched Ruby laser (7-10J/cm2 fluence at a repetition rate of 1Hz, 2-4mm spot size). Complete clearance was obtained in 131 patients, and hyperpigmentation was observed in 7%. Hypopigmentation persisted in 2.1% of the patients, and there was no recurrence after 6 months to 4.3 years of follow up (mean was 2.5 years). QS Nd:YAG laser was also used to treat ABNOM, and the rate of PIH was estimated to be between 50% and 73%.⁸ Our group showed that QS Alex laser is effective in the treatment of ABNOM. Post-operative pigmentary changes were frequent, and the use of topical bleaching agents was necessary to achieve a satisfactory result. The risk of transient hypopigmentation was high, and it affected up to 50% of the patients.⁹ More recently, a combination approach with a scanned carbon dioxide laser followed by a Q-switched Ruby laser has been found to be effective.¹⁰

Figure 1a:  Before laser treatment

Figure 1b: After 6 treatments with long pulse 532nm Nd:YAG (2ms, 6.5J/cm2, 2mm spot size) immediately followed by multiple passes of QS Alex (7.5J/cm2, 2mm spot size)

Melanocytic nevi are common, and often removed for cosmetic reasons. Various pigmented lasers have been used in their removal. A previous study using a QS Ruby laser found that an average clearance of 76% occurred after eight treatment sessions.10 However, recurrence can be a problem depending upon the depth of the nests of melanocytes. The use of a normal mode ruby laser (NMRL) for the treatment of melanocytic nevi is based upon the principle that with longer pulse durations, a greater degree of clearance is achieved when nests of cells are destroyed. A combined approach with a QS Ruby laser followed immediately, or 2 weeks later, with an NMRL has more recently been used with the intention of removing the superficial pigment first with the QS Ruby laser, thereby enhancing the penetration of the NMRL. A previous study found that although 52% of the nevi showed a visible reduction in pigment, no lesion had complete histological clearance. The short- and long-term histological findings of congenital nevi that have been treated with the NMRL indicated that subtle microscopic scars of up to 1mm in diameter are frequent. It has been proposed that such scars cover the underlying nevus cells, which leads to cosmetic improvement. Better cosmetic results were produced by first using an NMRL to remove the epidermis, immediately followed by multiple passes of a QS Ruby laser.¹¹ This approach effectively removes the epidermis, and in doing so enables a greater degree of penetration by the QS Ruby, of which multiple passes further enhance the clinical efficacy. A similar approach using a long-pulse pigmented laser immediately followed by multiple passes of a Q-switched pigmented laser can obtain similar results (see Figure 1).

Conclusion

For epidermal pigmented lesions, long-pulse pigmented laser or IPL can be effective with a lower risk of post-inflammatory hyperpigmentation, especially when used on dark-skinned patients. Q-switched laser is necessary to remove dermal pigment and tattoo in order to avoid the risk of scarring. A combination approach can be used for the removal of melanocytic nevi.

References

1. Huzaira M, Anderson RR. Magnetite tattoos. Lasers Surg Med 31(2):121-8 (2002).
2. Hu XH, Wooden WA, Vore SJ, Cariveau MJ, Fang Q, Kalmus GW. In vivo study of intradermal focusing for tattoo removal. Lasers Med Sci. 17(3):154-64 (2002).
3. Chan HH, Fung WKK, Ying SY, Kono T. An in vivo trial comparing the use of different types of 532nm Nd:YAG lasers in the treatment of facial lentigines in Oriental patients. Dermatol Surg 26(8):743-9 (2000 Aug).
4. Kawada A, Shiraishi H, Asai M, et al. Clinical improvement of solar lentigines and ephelides with an intense pulsed light source. Dermatol Surg 28(6):504-8 (2002 Jun).
5. Grossman MC, Anderson RR, Farinelli W, Flotte TJ, Grevelink JM. Treatment of cafe au lait macules with lasers. A clinicopathologic correlation. Arch Dermatol 131(12):1416-20 (1995 Dec).
6. Watanabe S, Takahashi H. Treatment of nevus of Ota with the Q-switched ruby laser. N Engl J Med 331(26):1745-50 (1994 Dec).
7. Kono T, Chan HH, Ercocen AR, et al. Use of Q-switched ruby laser in the treatment of nevus of ota in different age groups. Lasers Surg Med 32(5):391-5 (2003).
8. Kunachak S, Leelaudomlipi P, Sirikuchayanonta V.
   Q-switched ruby laser therapy of acquired bilateral nevus of Ota-like macules. Dermatol Surg 25(12):938-41 (1999 Dec).
9. Lam AY, Wong DS, Lam LK, Ho WS, Chan HH. A retrospective study on the efficacy and complications of Q-switched alexandritc laser in the treatment of acquited bilateral nevus of Ota-like macules. Dermatol Surg 25(12):938-41 (1999 Dec).
10. Manuskiatti W, Sivayathorn A, Leelaudomlipi P, Fitzpatrick RE. Treatment of acquired bilateral nevus of Ota-like macules (Hori’s nevus) using a combination of scanned carbon dioxide laser followed by Q-switched ruby laser. J Am Acad Dermatol 48(4):584-91 (2003 Apr).
11. Kono T, Nozaki M, Chan HH, Sasaki K, Kwon SC. Combined use of normal mode and Q-switched Ruby lasers in the treatment of congenital melanocytic nevi. Br J Plast Surg 54(7):640-3 (2001 Oct).