Cosmetic Medicine in Japan -東京大学美容外科- トレチノイン(レチノイン酸)療法、アンチエイジング(若返り)
Japanese pageEnglish page

Repeated treatment protocols for Melasma and Acquired Dermal Melanocytosis.

Kotaro Yoshimura, Katsujiro Sato, Emiko Aiba, Daisuke Matsumoto, Chiaki Machino, Takashi Nagase, Koichi Gonda, Isao Koshima.

Dermatologic Surgery, in press.

Background and Objective: Melasma and acquired dermal melanocytosis (ADM; acquired bilateral nevus of Ota-like macules) are both symmetrically seen most commonly on the face of women with darker skin, and are also known as difficult conditions to treat.
Methods: Our topical bleaching protocol with 0.1-0.4% tretinoin gel and 5% hydroquinone was repeatedly (1-3 times) performed for melasma (n=163), and a combination treatment with the topical bleaching and Q-switched ruby (QSR) laser was repeatedly (1-3 times) performed for ADM (n=62).
Results: There is a significant correlation between clinical results (clearance of pigmentation) and the number of sessions in both melasma (P=0.019) and ADM (P<0.0001).
Conclusion: The repeated treatment protocols for melasma and ADM showed successful clinical results compared to conventional ones, and they may be applied to other pigmented conditions. It may be better that epidermal and dermal pigmentations are treated separately, especially in dark-skinned peoples who are more likely to suffer post-inflammatory hyperpigmentation after inflammation-inducing therapies.

Melasma is acquired and symmetrical hypermelanosis, usually widely spread on the malar prominence and cheek, and less frequently on forehead and upper lip. Melasma appears usually in the thirties or forties after pregnancy or contraceptive use, suggesting that the triggering of melasma is hormonal related1. Conventional treatments for melasma include a sunscreen, hypopigmenting agents, often in combination with other therapies, such as tretinoin, topical corticosteroids, or superficial peeling agents2-7. On the other hand, acquired dermal melanocytosis (ADM) is a pigmented lesion involving bilateral grayish-brown facial macules that was first reported as acquired bilateral nevus of Ota-like macules (Hori’s nevus) by Hori et al.8. ADM onsets usually in the twenties, represents bilateral involvements, with the malar regions almost always affected while the lateral forehead and nasal alars are sometimes involved. The distribution pattern, its grayish round-spot appearance with unclear margins, and difference in color, are critical points to distinguish with melasma. Since both melasma and ADM are bilateral lesions and some patients have both, inexperienced doctors could misdiagnose them.
Melasma and ADM are frequently seen in Oriental females, and indeed 225 of 1,184 patients (19.1 %) who treated pigmented skin problems in our outpatient clinic had either or both. The authors previously described an aggressive and optimal use of tretinoin along with hydroquinone for various kinds of skin hyperpigmentation9-11 and a combination therapy with Q-switched ruby (QSR) laser for ADM12. The topical bleaching treatment with tretinoin and hydroquine is a most effective tool for removal of epidermal pigmentation. In this study, the clinical results of repeated therapies for melasma and ADM was analysed; we performed repeated tretinoin-hydroquinone bleaching therapy for melasma, and a repeated combination therapy of the topical bleaching and QSR laser for ADM.

Patients and Methods

Preparation of Ointments: Tretinoin aqueous gels (tretinoin gel) at 3 different concentrations (0.1, 0.2, and 0.4 %) were originally prepared at the Department of Pharmacy, University of Tokyo Hospital. The precise regimen of tretinoin aqueous gel was described before10. These gels can be prepared relatively easily, because the tretinoin powder (Sigma Chemical, St. Louis, MO) is commercially available. Aqueous gel is most suitable for ointment base of tretinoin because of its good permeability. An ointment including 5% hydroquinone and 7% lactic acid (HQ-LA ointment), and one including 5% hydroquinone and 7% ascorbic acid (HQ-AA ointment) were also prepared. Plastibase? (petrolatum polyethylene ointment base, Taisho Pharmacology, Osaka, Japan) was used as the ointment base of the HQ-LA ointment, while hydrophilic ointment was used for the HQ-AA ointment. Because tretinoin gel, HQ-LA, and HQ-AA ointments (especially tretinoin gel) are pharmacologically unstable, fresh ointments were prepared at least once a month and stored in a dark and cool (4oC) place.
Evaluations of results: Photographs were taken for every patient at baseline and after treatment with a high-resolution digital camera (Canon EOS-D30). The percentage of pigmentary clearance was evaluated via the photographs by two experienced plastic surgeons who did not perform this treatment. The mean data of the pigmentary clearance of each patient were classified into 4 categories: “excellent” (80% or more clearance), “good” (50% to less than 80% clearance), “fair” (0% to less than 50% clearance), and “poor” (no change or worse).
Patients: Of 1,184 Asian patients who underwent cosmetic treatments, 163 had melasma and 62 suffered from ADM (6 had also melasma). All patients with melasma or ADM were women except for 2 men with melasma. Patient age at the start of the treatment of melasma and ADM patients ranged from 27 to 62 years (42.3 ±7.1; mean ± S.D.) and from 22 to 53 years (36.4 ±8.1), respectively.
Treatment Methods: For melasma, our topical bleaching treatment (see below) was performed. If patients wanted, the treatment was repeated two or three times. For ADM, a combination therapy of the topical bleaching and QSR laser was performed. The number of treatment sessions depends on patient’s decision. Typical time courses of the treatment protocols are shown in Fig.1a and 1b.
1) Topical bleaching treatment: The purpose of this treatment is to improve epidermal pigmentation by accelerating discharge of epidermal melanin (with tretinoin) and suppressing new epidermal melanogenesis (with hydroquinone). The two-staged (bleaching and healing) treatment was performed as following:
a) Bleaching phase: 0.1 % tretinoin gel and HQ-LA ointment were initially applied to the skin lesions twice a day. Tretinoin gel was carefully applied only on pigmented spots using a small cotton-tip applicator, while the HQ-LA ointment was widely applied with fingers (e.g. all over the face) a few minutes later, after allowing the applied tretinoin aqueous gel get to dry. The method of ointment application is critical in this aggressive treatment in order to obtain maximal bleaching effects with minimal irritant dermatitis. In cases in which severe irritant dermatitis was induced by HQ-LA ointment, HQ-AA ointment was used instead. Patients were requested to visit our hospital at 1, 2, 4, 6 and 8 weeks after starting this treatment, and every 4 weeks thereafter. When the appropriate skin reaction (that is, mild erythema and scaling) was not observed at 1 week, the concentration of tretinoin was increased to 0.4 %, because 0.2% tretinoin gel was usually not strong enough to get a sufficient reaction in these cases. The concentration of tretinoin and frequency of its application were appropriately modified according to the skin condition and degree of erythema and scaling. It took 4 to 8 weeks to finish this phase. In the second or third bleaching treatment, tretinoin gel of the final strength used in the first step was used from the beginning.
b) Healing phase: After a 4-8 week bleaching phase, the application of tretinoin gel and HQ-LA ointment was discontinued, and application of HQ-AA ointment was started in order to prevent post-inflammatory hyperpigmentation (PIH) until the redness was sufficiently reduced. It usually took 4 weeks to complete this phase. Topical corticosteroids were not employed in either the bleaching or healing phase.
2) QSR laser treatment: In patients with ADM, topical anesthesia (lidocaine patch; PenlesR, Wyeth Lederle Japan Inc., Tokyo, Japan) was applied 60-120 minutes before the laser treatment. For QSR 694.5 nm laser (Model IB101, Niic Co. LTD, Tokyo, Japan) treatment, spot size of 5 mm, 1 Hz repeat rate, pulse duration of 20 ns, and fluences ranged from 4.0 to 5.0 J/m2 were used. After laser treatment, topical gentamicin sulfate ointment (GentacinR, Schering-Plough, NJ) was applied twice a day until a scale or thin crust disappeared (usually 5-7 days). At 2 weeks after laser treatment, application of HQ-AA ointment was started.
At 4 weeks after each laser treatment, topical bleaching treatment with tretinoin gel of appropriate concentration (usually the same as the final concentration in the bleaching phase) and HQ-AA ointment were started as a pretreatment of the next laser irradiation, and also as a treatment of post-laser PIH in some cases. In most cases, a bleaching phase for 2 weeks was sufficient, and we can usually estimate the clinical result at 8 weeks after each laser treatment. When some hyperpigmentation remained, we can do another session.
Statistics: Spearman’s correlation coefficient by rank test was used for analyzing a statistical significance between the extent of clinical improvements and the number of treatments.

In 163 patients with melasma, 96 underwent only one topical bleaching treatment (See Fig.1a) with excellent results in 25 and good in 40; 56 underwent two treatments with excellent results in 21 and good in 20; 11 underwent three treatments with excellent results in 7 and good in 3 (Table 1). In 62 patients with ADM, 16 underwent only one treatment (a combination of topical bleaching and QSR laser; See Fig.1b) with excellent results in 1 and good in 6; 26 underwent two treatments with excellent results in 14 and good in 8; and 20 underwent three treatments with excellent results in 17 and good in 3 (Table 2).
Representative cases with melasma are shown in Figs. 2 and 3, and those with ADM in Figs. 4 and 5.
Statistical analysis showed there is a significant correlation between clinical results (clearance of pigmentation) and the number of sessions in both melasma (P=0.019) and ADM (P<0.0001).

The authors previously reported on a topical bleaching therapy with aggressive use of retinoids in aqueous gel only on the pigmented spot and use of hydroquinone all over the face12,13. The treatment can clear only epidermal pigmentation, but with excellent efficiency compared to other conventional treatments such as AHA peeling or single use of tretinoin or hydroquinone. Corticosteroids are not used in the bleaching protocol, and, furthermore, tretinoin is not continually used over 2 months. It is well known that long term continual use of tretinoin, either topical or oral, reduces clinical effects of tretinoin14,15. It has been suggested that this phenomenon may be due to intracellular production of cellular retinoic acid binding proteins (CRABPs) which is induced by the retinoid signal. This is why we use repeated bleaching protocols with intervals instead of continual use of tretinoin.
The present results demonstrated that the results for ADM (excellent cases; excellent and good cases = 6.3%; 43.8%) are not as good as for melasma (26.0%; 67.7%) in one-session cases, but in three-session cases ADM was improved at a higher rate (85.0%; 100%) compared to melasma (63.6%; 90.9%). Actually, we often detected apparent improvement during the second session in cases with ADM.
Melasma usually has most of its pigmentation in the epidermis (Fig. 6). Although previous reports with tretinoin, hydroquinone, AHA or others, or combinations of multiple agents, showed moderate to relatively good clearance of melasma2-7, complete clearance of pigmentation is rare. Based on our experiences, the differential uses of tretinoin and hydroquinone are quite important for melasma, because if we use tretinoin on a larger area such as the whole face, the surrounding non-pigmented area is also bleached, and consequently, the macules would remain clinically recognizable. Although melasma is well-known as a hard condition to treat, repetition of the topical bleaching only on the pigmented area improved it completely in some cases.
ADM has significant epidermal pigmentation, unlike nevus of Ota, (Fig.6) and the fact suggests that clearance of epidermal pigmentation before QSR treatment is important in order to promote the efficiency of QSR laser for dermal melanocytosis and to reduce PIH induced by inflammation around the basal layer12. Topical bleaching treatment clears post-inflammatory hyperpigmentation induced by the QSR laser and also plays an important role as a pretreatment for the next QSR irradiation.
The bleaching pretreatment for QSR laser therapy can be applied to any other skin conditions with both epidermal and dermal pigmentation, such as friction melanosis and pigmented contact (cosmetic) dermatitis. One typical case with pigmented contact dermatitis is shown in Fig. 7 as a reference supplement. Compared to lesions with dermal melanocytosis, those with dermal melanosis were frequently treated with fewer QSR sessions.
Melasma and ADM are sometimes hard to distinguish each other because they are both symmetrical, and they coexist in some cases. Indeed, we have a few cases in our series which were first diagnosed as melasma, but dermal pigmentation was found after the first topical bleaching and the diagnosis was corrected to ADM later. In our repeated protocols the topical bleaching treatment can be started in either condition, so that the treatment plan can be corrected without any loss of treatment periods.
We here proposed repeated treatment protocols for melasma and ADM with successful effectiveness compared to conventional ones, and they may be applied to other pigmented conditions. It may be better that epidermal and dermal pigmentations are treated separately, especially in dark-skinned people who are more likely to suffer PIH after inflammation-inducing therapies.

Figure Legends

Fig. 1. (a) A representative time course of our topical bleaching treatment with tretinoin and hydroquinone. Tretinoin is used for 6 weeks in each bleaching phase, and can be restarted with an at least 4 weeks interval of healing phase.

(b) A representative time course of the combined treatment. Tretinoin is used for 4 weeks in the initial bleaching pretreatment, and for 2 weeks in the following pretreatments. If QSR laser treatment is performed 3 times, and the total treatment period is 32 weeks.

Fig. 2. Case1. (top) Baseline photo of a 47-year-old woman with melasma. (bottom) At 5 months, the pigmentation was cleared up after 3 sessions of topical bleaching treatments.

Fig. 3. Case2. (top, left & right) A baseline view of a 27-year-old woman with melasma. (bottom, left & right) At 5 months, after 2 sessions of QSR laser and topical treatments. The clinical result was evaluated as “excellent”.

Fig. 4. Case3. (top) A baseline view of a 41-year-old woman with ADM. (bottom) Two months after the 3rd QSR laser treatment (8 months from the baseline). The result of the clearance was evaluated as “excellent”.

Fig. 5. Case 4. (left) A baseline view of a 49-year-old woman with ADM. She had spotty pigmentations on the cheeks, lateral foreheads, and nasal alars. (right) After 3 sessions of QSR laser and topical treatments (32 weeks from the baseline). The pigmentations were almost completely cleared and also the yellowish color of surrounding skin has changed to pinkish.

Fig. 6. Histology of melasma (left) and ADM (right) before treatment. Melasma demonstrated epidermal hyperpigmentation around the basal layer and very few in the dermis, while ADM showed melanocytosis in the upper dermis, as well as hyperpigmentation of the basal layer. (Masson-Fontana staining; 100X)

Fig. 7. Case 5. This is not a case included in the present study and only shown as a supplement for reference. (left) Histology of pigmented contact (cosmetic) dermatitis before treatment. The basement membrane is broken down and a number of melanosomes were dropped into the dermis (melanin incontinence). (Masson-Fontana staining; 200X) (middle) At baseline, the patient showed dark brown to dark grey macules distributed symmetrically on a wide area of the face. The combined therapy of QSR laser and topical bleaching was performed. (right) At 4 months (one session of QSR laser treatment with pre- and post-treatment of topical bleaching), the pigmentation topical bleaching pretreatment. The pigmentations were significantly improved by only one session of the combined treatment. It may be that dermal melanosis is easier to treat by laser than dermal melanocytosis.

Table1. Clinical results of cases with melasma.

Table 2. Clinical results of cases with ADM.


1. Grimes PE. Melasma. Etiologic and therapeutic considerations. Arch Dermatol 1995;131,1453-7.
2. Hurley ME, Guevara IL, Gonzales M, Pandya AG. Efficacy of glycolic acid peels in the treatment of melasma. Arch Dermatol 2002;138.1578-82.
3. Griffiths CE, Finkel LJ, Ditre CM, Hamilton TA, Ellis CN, Voorhees JJ. Topical tretinoin (retinoic acid) improves melasma. A vehicle-controlled, clinical trial. Br J Dermatol 1993;129:415-21.
4. Nanda S, Grover C, Reddy BS. Efficacy of hydroquinone (2%) versus tretinoin (0.025%) as adjunct topical agents for chemical peeling in patients of melasma. Dermatol Surg 2004;30:385-8.
5. Sarkar R, Bhalla M, Kanwar AJ. A comparative study of 20% azelaic acid cream monotherapy versus a sequential therapy in the treatment of melasma in dark-skinned patients. Dermatology 2002;205:249-54.
6. Lawrence N, Cox SE, Brody HJ. Treatment of melasma with Jessner's solution versus glycolic acid: a comparison of clinical efficacy and evaluation of the predictive ability of Wood's light examination. J Am Acad Dermatol 1997;36:589-93.
7. Garcia A, Fulton JE Jr. The combination of glycolic acid and hydroquinone or kojic acid for the treatment of melasma and related conditions. Dermatol Surg 1996;22:443-7.
8. Hori Y, Kawashima M, Oohara K, Kukita A. Acquired, bilateral nevus of Ota-like macules. J Am Acad Dermatol 1984;10:961-4.
9. Yoshimura K, Harii K, Aoyama T, et al. A new bleaching protocol for hyperpigmented skin lesions with a high concentration of all-trans retinoic acid aqueous gel. Aesthetic Plast Surg 1999;23:285-91.
10. Yoshimura K, Harii K, Aoyama T, Iga T. Experience with a strong bleaching treatment for skin hyperpigmentation in Orientals. Plast Reconstr Surg 2000;105:1097-108.
11. Yoshimura K, Momosawa A, Watanabe A, et al. Cosmetic color improvement of the nipple-areola complex by optimal use of tretinoin and hydroquinone. Dermatol Surg 2002;28:1153-8.
12. 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 2003;29:1001-7.
13. Yoshimura K, Momosawa A, Aiba E, et al. Clinical trial of bleaching treatment with 10 % all-trans retinol gel. Dermatol Surg 2003;29:155-60.
14. Muindi J, Frankel SR, Miller WH Jr, et al. Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia. Blood. 1992;79:299-303.
15. Regazzi MB, Iacona I, Gervasutti C, Lazzarino M, Toma S. Clinical pharmacokinetics of tretinoin. Clin Pharmacokinet 1997;32:382-402.

Copyright -Cosmetic Medicine in Japan- 東大病院美容外科、トレチノイン(レチノイン酸)療法、アンチエイジング(若返り)