Treatment of reticulate acropigmentation of Kitamura with azelaic acid

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3. 4. 5. 6.

7.

8. 9.

cell lymphoma: a clinicopathologic study of 41 cases. Am J Surg Pathol 1990;14:439-48. Berti E, Gianotti R, Alessi E. Primary anaplastic large cell lymphoma of the skin. Dermatologica 1989;178:225-7. Kadin ME, Sako D, Berliner N, et al. Childhood Ki-1 lymphoma presenting with skin lesions and peripheral lymphadenopathy. Blood 1986;68:1042-9. Agnarsson BA, Kadin ME. Ki-1 positive large cell lymphoma: a morphologic and immunologic study of 19 cases. Am J Surg Pathol 1988;12:264-74. Murphy SB. Classification, staging and end results of treatment of childhood non-Hodgkin's lymphomas: dissimilarities from lymphomas in adults. Semin Oncol 1980; 8:332-9. Heitger A, Gadner H, Bucsky P, et al. Large cell anaplastic lymphoma in childhood-clinics and therapy resuRs in a newly defined histopathologieal entity. Kiln P~idiatr 1989; 201:237-41. Stansfeld AG, Diebold J, Kapanci Y, et al. Updated Kiel classification for lymphomas. Lancet 1988;1:292-3. Schnitzer B, Roth MS, Hyder DM, et al. Ki-l lymphomas in children. Cancer 1988;61:1213-21.

Primary cutaneous large-cell anaplastic Iymphoma 10. Banerjee SS, Herald J, Harris M. Twelve cases of Ki-I positive anaplastic large cell lymphoma of the skin. J Clin Pathol 1991;44:119-25. 11. Chan JKC, Ng CS, HuiPK, et al. Anaplastie large cell KM lymphoma: delineation of two morphological types. Histepatho/ogy 1989;15:11-34. 12. Kaudewitz P, Stein H, Dallenbach F, et al. Primary and secondary cutaneous Ki-1 + (CD 30+) anaplastic large cell lymphomas: morphologic, immunohistologic, and clinical characteristics. Am J Pathol 1989;135:359-67. 13. Ralfkiaer E, Bosq J, Gatter KC, et al. Expression of a Hodgkin and Reed-Stern berg cell associated antigen (Ki- 1) in cutaneous lymphoid infiltrates. Arch Dermatol Res 1987;279:285-92. 14. Van der Putte SCJ, Toonstra J, Van Wiehen DF, et al. The expression of the Hodgkin's disease-associated antigen Ki- 1 in cutaneous infiltrates. Acta Derm Venereol (Stockh) 1988;68:202-8. 15. Banks PM, Metter J, Allred DC. Anaplastic large cell (Ki-1) lymphoma with histiocytic phenotype simulating carcinoma. Am J Clin Pathol 1990;94:445-52.

Treatment of reticulate acropigmentation of Kitamura with azelaic acid An immunohistochemical and electron microscopic study Koichiro Kameyama, MD, PhD, a Mikako Morita, MD, a Kazue Sugaya, MD, PhD, a Shigeo Nishiyama, MD, PhD, a and Vincent J. Hearing, PhD b Sagamihara, Japan,

and Bethesda, Maryland No successful therapy has been reported for reticulate acropigmentation of Kitamura, which is an autosomal dominant dermatosis. We treated a patient with 20% azelaic acid ointment. Within several weeks the pigmentation was remarkably decreased and no side effects were observed. Histologic examination revealed an increased number of dopa-positive melanocytes. These cells reacted strongly to staining with antityrosinase antibody or antityrosinaserelated protein antibody. Electron microscopic findings showed many melanosomes within melanocytes, keratinocytes, and melanophages. These findings suggest that the hyperpigmentation of reticulate acropigmentation of Kitamura is the result of an excess amount of melanin production caused by activation of melanocytes in the basal layer. (J AM ACAD DERMATOL 1992;26:817-20.) Reticulate acropigmentation of Kitamura (RAPK) was first described in Japan in 1943.1 It is From the Department of Dermatology,Kitasato UniversitySchoolof Medicine,a and the Laboratoryof Cell Biology,National Institutes of Health) Reprint requests: KolchiroKameyama, MD, Department of Dermatology,Kitasato UniversitySchoolof Medicine, 1-15-1Kitasato,Sagamihara 228, Japan.

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characterized by reticulate, brown maeules on the dorsum of the hands and feet and by "pits" on the palms. Cases of R A P K have recently been reported from other countries)' ~ Initially R A P K was reported to manifest reticulate pigmentation only on the extensor surface of the extremities.l However, 28 of 49 patients with R A P K in Japan 4 have had pigmentation on the entire body. In 1978 azelaic acid (AZA, C9 dicarboxylic acid) was identified in cul817

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Kameyama et al.

and one of her three brothers have the same clinical manifestations. Physical examination revealed brown, reticulate macules on her entire body; she also had numerous pits and breakage of the epidermal ridge pattern on the palms. Most of the pigmented macules measured less than 5 mm and were slightly depressed (Fig. 1). Routine laboratory findings and levels of adrenocorticotropic hormone, o~-melanocyte-stimulating hormone (MSH), and/3-endorphin were normal. A biopsy specimen from the patient's neck was cut into three pieces: one for light microscopic examination, one for electron microscopic examination, and one for the dopa reaction and immunohistochemical staining. Frozen sections were incubated for 6 hours with antityrosinase antibody, antiPEP7, 9 or antityrosinase-related protein (anti-TRP1), TMH1, t~ with a Dako Corp. staining kit (Carpenteria, Calif.). RESULTS ""

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Fig. 1. Brown to black, round or irregularly angled, slightly depressed pigmented macules on face and neck. Fig. 2. Immunohistochemical staining with antityrosinase antibody, anti-PEP7.

tures of Pityrosporum. 5 A Z A is a competitive inhibitor of tyrosinase in vitro and has beneficial effects in the treatment of chloasma and lentigo maligna.6, 7 Tyrosinase is a key enzyme in melanin production. 8 Therefore A Z A might prove useful in the therapy of RAPK. In this study we report that the hyperpigmentation in R A P K is the result of activation of melanocytes and that A Z A produces clinical benefits in patients with RAPK. CASE REPORT

A 50-year-old Japanese woman has had progressively spreading hyperpigmentation since puberty. Her father

Light microscopic examination revealed that the epidermis of the lesions had various degrees of atrophy, elongated rete ridges with large amounts of melanin, and increased numbers of clear cells. Pigmented papillae were seen in the basal layer, but no inflammatory cells were observed in the papillary dermis. Some spindle-shaped cells that contained brown granules were seen in the papillary dermis. Staining revealed an excess of dopa-positive cells in the basal region. Immunohistochemical staining revealed that these dopa-positive clear cells were tyrosinase and TRP1 positive (Fig. 2). Some keratinocytes and melanophages were also stained with these antibodies. Electron microscopic examination revealed an increased number of melanocytes in the basal cell layer, and numerous melanosomes were observed within keratinocytes (Fig. 3). Dendrites of melanophages in the papillary dermis contained large numbers of melanosomes or melanosome complexes but no premelanosomes. The degree of hyperpigmentation decreased after the patient applied 20% A Z A ointment to her face, neck, and hands twice a day for several weeks. In order to compare the degree of pigmentation in treated and untreated skin, A Z A ointment was applied twice a day to the patient's left knee, while the right knee was untreated. After 2 weeks the degree of pigmentation was less in her left knee than in her right knee. After 2 months of treatment with A Z A ointment the brown macules on her face were remarkably decreased (Fig. 4). Skin irritation was not observed.

Volume26 Nmnber 5, Part 2 May 1992

Azelaie acid and reticulate acropigmentation

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DISCUSSION Our histologic findings show that melanin production and its transfer to keratinocytes was greatly increased in a patient with RAPK. Many factors that increase melanin production have recently been described, including interferon, It the number of the M S H receptor, 12 MSH, 13 the dopachrome conversiorl factor, 14 and prostaglandins. 15 In this patient, however, no evidence of inflammation or an endocrine abnormality was observed. The pathogenesis of R A P K is still unknown. R A P K is inherited as an autosomal dominant disorder, and Kitamura et al. 16 suggested that RAPK is a type of nevus. It has recently become clear that melanin production is regulated by a balance between positive factors, such as the dopachrome conversion factor, t4, t7 and negative factors, such as the inhibitor of tyrosinase.18 Tyrosinase is a key enzyme of melanin production, and another enzyme, TRP1, has recently been reported to play an important role in melanin production? Amelanotic melanocytes are not stained by anti-TRP1 antibody.19 We have reported that a positive correlation exists between melanin production and the fluorescence intensity of TRP 1 in murine melanoma cells, t8 and we have already confirmed the same phenomenon with the use of antityrosinase antibody (data not shown). Therefore a reaction to staining of melanocytes with antityrosinase antibody or by anti-TRP1 antibody confirms the activation of melanocytes in melanin production in a patient with RAPK. Some keratinocytes and melanophages were also stained by these antibodies, because these enzymes were transferred with melanosomes from melanocytes.

Fig. 4. After treatment with 20% AZA ointment for 2 months.

We have reported that in amelanotic murine J B / M S - W melanoma cells, a competitive inhibitor of tyrosinase overcomes the activity of tyrosinase, is Therefore we decided to use the tyrosinase inhibitor A Z A in a patient with RAPK. A Z A showed a clinical effect within 2 weeks. These results suggest that the activity of tyrosinase is increased in patients with RAPK. In addition to being a competitive inhibitor of tyrosinase, A Z A is toxic for h u m a n lymphocytes, murine fibroblasts, 2~ and murine and human melanoma cells. 21 Its cytotoxic effect is thought to be related to an antimitochondrial action. 22, 23 Both met-

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K a r n e y a m a et al.

abolie s t u d i e s 24 and isolated mitochondria 22 have shown t h a t dicarboxylic acids undergo 13-Oxidation and m u s t t h e r e f o r e enter the mitochondria. Furt h e r m o r e t h e y have b e e n shown to inhibit cell respiration b y competitive inhibition of mitochondrial o x i d o r e d u c t a s e s such as reduced nicotirtamide adenine d i n u c l e o t i d e dehydrogenase, succinic dehydrogenase, a n d r e d u c e d ubiquinone-cyt-c-oxido-reductase. 29 A Z A penetrates t u m o r ceils two to three times m o r e quickly t h a n normal ceils of the corresponding lines. T h e degree o f toxicity for t u m o r cells is p r o p o r t i o n a l to the u p t a k e o f the diacid. 2~A Z A is selectively cytotoxic to malignant melanogenic melanocytes b u t not to n o r m a l pigmented cells or to a m e l a n o t i e o r nonmelanogenic m e l a n o m a cells. 25 These r e p o r t s suggest that melanocytes in a patient with R A P K are metabolically activated, especially with r e g a r d to melanin production. Although we did not c o m p a r e t h e n u m b e r of rnelanocytes in affected and n o n a f f e c t e d areas, the n u m b e r of melanocytes in affected a r e a s seemed to be increased. This finding m a y s u g g e s t t h a t A Z A ointment suppressed the p r o l i f e r a t i o n o f melanocytes in affected areas. As expected, w h e n this patient stopped applying A Z A her p i g m e n t a t i o n increased rapidly, but responded quickly t o r e p e a t t r e a t m e n t with A Z A .

REFERENCES 1. Kitamura K, Akamatu S. Pigmentary disorders. Rinsho Hifu-Hitsunyo 1943;8:201-4. 2. Griffiths WAD. Retieulateacropigmentation of Kitamura. Br J Dermatol 1976;95:437-43. 3. Woodley DT, Caro I, Wheeler CE. Reticulate acropigmentation of Kitamura. Arch Dermatol 1979;I 15:760-1. 4. Kanamoto Y, Ikenaga M, Kosuge M, et al. Reticulate acropigmentation of Kitamura. Rinsho Hihuka 1982;36:4754. 5. Nazzaro-Porro M, Passi S. Identification of tyrosinase inhibitors in culture ofpityrosporum. J Invest Dermato119781 7i:205-8. 6. Breathnach AC, Nazzaro-Porro M, Passi S, et al. Azelaie acid therapy in disorders of pigmentation. Clin Dermatol 1989;7:106-19. 7. Rowell-Verailo VM, Verallo V, Graupe K, et al. Doubleblind comparison of azelaic acid and hydroquinone in the treatment of melasma. Acta Derm Venereol (Stockh) 1989;I43 (suppl):58-61. 8. Hearing VJ. Mammalian monophenol monooxygenase (tyrosinase): purification, properties and reactions catalyzed. In: Kaufman S, ed. Methods in enzymology. New York: Academic Press, 1987:154-65.

Journal of the American Academy of Dermatology 9. Jimenez M, Tsukamoto S, Hearing VJ. Tyrosinases from two different loci are expressed by normal and by transformed melanocytes. J Biol Chem 266;1991:1147-56. 10. Tomita Y, Sibahara S, Takeda A, et al. The monoclonal antibodies TMH-1 and TMH-2 specially bind to a protein encoded at the murine b-locus, not to the authentic tyrosinase encoded at the e-locus. J Invest Dermatol 1991; 96:500-4. 11. Kameyama K, Tanaka S, Yasuo Ishida, et al. Interferons modulate the expressionof hormone receptors on the surface of murine melanoma cells. J Clin Invest 1989;83:21321. 12. Kameyama K, Montague PM, Hearing VJ. Expression of melanocyte stimulating hormone receptors correlates with mammalian pigmentation, and can be modulated by interferons. J Cell Physiol 1988;137:35-44. 13. Wong G, Pawlek J. Melanocyte-stimulating hormone promotes activation of pre-existing tyrosinase molecules in Cloudman $91 melanoma cells. Nature 1975;255:644-6. 14. Hearing VJ, Korner AM, Pawlek JM. New regulator of melanogenesis are associated with purified tyrosinase isozymes. J Invest Dermatol 1982;79:16-8. 15. Abdel-Malek ZA, Swope VB, Amornisiripanitch, et al. In vitro modulation of proliferation and melanization of S91 melanoma ceUs by prostaglandins. Cancer Res 1987; 47:3141-6. 16. Kitamura K, Akamatsu S, Hirokawa K. Eine besondere Form der Akropiganentation: acropigmentatio reticularis. Hautarzt 1953;4:152-6. 17. Korner AM, Gettins P. Synthesis in vitro of 5,6-dLhydroxy2-carboxilic acid by dopachrome conversion factor from Cloudman $91 melanoma cells. J Invest Dermatol 1985; 85:229-3 l. 18. Kameyama K, Jimenez M, Muller J, et al. Regulation of mammalian melanogenesis by tyrosinase inhibition. Differentiation 1989;42:28-36. 19. Tomita Y, MontaguePM, Heating VJ. Anti-T4-tyrosinase monoclonal antibodies-specificmarker for pigmented melanocytes. J Invest Dermatol 1985;85:426-30. 20. Picardo M, Passi S, Sirianni MC, et al. Activity of azelaic acid on cultures of lymphoma- and leukemia-derived cell lines, normal resting and stimulated lymphocytes and 3T3 fibroblasts. Biochemical Pharmacol 1985;34:1653-8. 21. Leibl H, Stingl G, Pehamberger H, et al. Inhibition ofDNA synthesis of melanoma cells by azelaic acid. J Invest Dermatol 1985;85:417-22. 22. Picardo M, Passi S, Nazzaro-Porro M, et al. Effect of medium chain length dicarboxylieacids on mitoehondrial respiration. J Invest Dermatol 1983;80:350. 23. Passi S, Picardo M, Nazzaro-Porro M, et al. Antimitochondrial effect of saturated medium chain length (C8C13) dicarboxilic acids. Biochem Pharmacol 1984; 33:103-8. 24. Passi S, Nazzaro-Porro M, Picardo M, et al. Metabolism of straight, saturated, medium chain-length (C9-C12) dicarboxilic acid. J Lipid Res 1983;24:1140-7. 25. Hu F, Mah K, Temamura DJ. Effects of dicarboxylic acids on normal and malignant melanocytes in culture. Br J Dermatol 1986;114:17-26.