ELECTRON MICROSCOPIC STUDY OF MELANIN-PHAGOCYTOSIS BY CUTANEOUS VESSELS IN CELLULAR BLUE NEVUS*

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1 THE JOURNAL 05' INVESTIGATIVE DERMATOLOGY Copyright 1969 by The Williams & Wilkinl Co. Vol. 62, No. 6 Printed in U.S.A. ELECTRON MICROSCOPIC STUDY OF MELANIN-PHAGOCYTOSIS BY CUTANEOUS VESSELS IN CELLULAR BLUE NEVUS* SYOZO SATO, M.D. AND ATSUSHI KUKITA, M.D. ABSTRACT Skin lesions of two cases of cellular blue nevus were observed with an electron microscope and the phagocytized melanosomes and premelanosomes in the endothelial cells and pericytes of the cutaneous vessels are described. It is considered that the small vessels of the human skin participate in the degradation of the melanosomes and premelanosomes in certain pathological conditions. It has been reported that melanosomes produced in melanocytes of human skin are eliminated from the skin or degraded after they are transferred to keratinocytes 1, 2), Langerhans' cells (3 8), melanophages (1, 2), Schwann cells (9) or macrophages of the regional lymph nodes (10). Autophagocytosis and degradation of the premelanosomes and melanosomes in the melanocytes and actively melanin-synthesizing cells in the dermis have also been observed (11, 12). In this paper, the authors report an electron microscopic study of cellular blue nevus with special reference to the melanosomes and premelanosomes phagocytized or degraded by the cutaneous vessels. MATERIALS AND METHODS Biopsy specimens excised from the lesions of two cases of cellular blue nevus were used. The specimens were cut into small pieces, fixed in two per cent osmium tetroxide with phosphate buffer at ph 7.4, dehydrated through gradually increasing concentrations of ethanol, immersed in propylene oxide, and embedded in Epon 812 (13). TJltrathin sections were made with a Du Pont diamond knife attached to a Porter-Blum ultramicrotome MT-2. The sections were then stained with uranyl acetate and lead citrate (14) and were observed in a Hitachi HU 11A electron microscope. RESULTS The melanosomes and premelanosomes were phagocytized by the cutaneous vessels, nevus cell-like cells and melanophages in the curium of the diseased skin. The venules, approximately 50 microns in the diameter, have a capillary-like This study was supported by a grant from the Ministry of Education, Japan, and the Far East Basic Research Fund of Sears, Roebuck and Co., Inc., Chicago, Illinois. Received September 21, 1968; accepted for publication December 3, * From The Department of Dermatology, Sapporo Medical College, Sapporo, Japan. 528 structure (continuous thick endothelial cells) and are surrounded by several layers of basement membrane and a number of pericytes. Outside of the basement membrane, perivascular phagocytes with well developed rough surfaced endoplasinic reticulum and phagocytic vacuoles were observed. Several melanosomes and premelanosomes were aggregated in the phagocytic vacuoles of the endothelial cells (Fig. 1), pencvtes (Fig. 2), and perivascular phagocytes (Fig. 3). No melanin phagocytosis by the endothelium of the capillary was recognized. A great number of melariosomes and premelanosomes were observed in the dermal melanocytes and melaninsynthesizing cells. The melanosomes and premelanosomes phagocytized by the vascular wall were easily discernible from the other granules of high electron densitv. According to the degree of melanization, various degradation processes were observed in the phagocytic vacuoles. The premelanosomes lost the limiting membrane, and the less melanized skeletal structure was broken up into small pieces with a decrease in their electron density. The degradation of the melanosomes was minimal. No free melanosomes and premelanosomes were found in the basement membrane, in the gap between two endothelial cells, or around the penicytes. Degenerative changes of the vascular wall were not detectable. DISCUSSION It is generally accepted that blood vessels which do not belong to the reticuloendothelial system perform phagocytic functions (15). Cotran (16) confirmed that the endothelium of the vessels are phagocytic. In his experiment, rats and mice were overloaded with intravenous carbon black and phagocytic bodies appeared in the endothelial cells of the cutaneous vessels.

2 MELANIN-PHAGOCYTOSIS BY CUTANEOUS VESSELS 529 S. S : & 5' Fio. 1. Portion of the endothelial cells of the venule, showing numerous phagocytic vacuoles with melanosomes and premelansomes. Endothelial cell (E), Vascular lumen (L), Pericyte (P). X 15,000

3 530 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY wwi!jwfta I &a Fic. 2. Melanosomes phagocytized in the perieyte are shown. Endothelial cell (E), Vascular lumen (J), Pericyte (F), Basement membrane (EM). >< 15,000

4 MELANIN-PHAGOCYTOS1S BY CUTANEOUS VESSELS 31 L L:t_?r,zb j.wp I'. 0..fl Fic. 3. Two perivascular phagocytes between the vessel (upper right corner of the electron micrograph) and the nevus cell-like cell (bottom) are occupied by single membrane bound lysosomal granules containing degraded premelanosomes. No phagocytic body is found in the vascular wall. Endothelial cell (E), Perivascular phagocyte (PP), Nevus celllike cell (NC). X 15,000

5 532 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY Electron microscopic studies (17 19) of patients with Fabry's disease showed intracellular accumulations of a lipid substance in the endothelial cells and pericytes of cutaneous vessels. Zelickson (20) reported many large dense granules within pericytes and endothelium in the dermal capillaries in patients receiving prolonged and high doses of chlorpromazine. In the present study, we may say that the melanosomes and premelanosomes synthesized in the dermal melanocytes and nevus cell-like cells are phagocytized by the pericytes and endothelium of the cutaneous vessels. However, the dynamics of the phagoeytie processes were not demonstrated. The authors conclude that the small vessels which phagoeytize melanosomes and premelanosomes correspond to the venules (15, 21, 22). The pathological significance of the intramural depot in the endothelial cells of the venules is obscure. These findings may relate to the fact that the venules are physiologically more permeable than the capillaries or arterioles, and are more susceptible than capillaries to vasoreaetive agents or to extrinsic stimulations (15). REFERENCES 1. Droehmans, P.: Melanin granules: Their fine structure, formation, and degradation in normal and pathological tissues. Internat. Rev. Exp. Path., 2: 357, Mishima, Y.: Macromolecular changes in pigmentary disorders. Arch. Derm., 91: 519, Zeliekson, A. S.: The Langerhans' cells. J. Invest. Derm., 44: 201, Breathnaeh, A. S. and Wyllie, L. M.: Melanin in Langerhans' cells. J. Invest. Berm., 45: 401, Mishima, Y.: Melanosomes in phagocytic vacuoles in Langerhans' cells. J. Cell Biol., 30: 417, Zelickson, A. S.: Melanocyte, melanin granule, and Langerhans cell, p. 163, Ultrastructure of Normal and Abnormal Skin. Lea & Febiger, Philadelphia, Breathaach, A. S. and Wyllie, L. M.: The problem of the Langerhans' cells, p. 97, Advances in Biology of Skin, Vol. 8. Ed., Montagna, W., Oxford, Pergamon Press, Sato, S. and Takahashi, M.: Electron microscope study on Langerhans cells with melamn granules. Jap. 5. Bermat:, 78: In press. 9. Mishima, Y.: Electron microscopy of human cutaneous nerve pigmentation. Brit. J. Berm., 79: 611, Sato, S., Jimbow, K. and Kukita, A.: Unpublished data. 11. Kawamura, T., Ikeda, S., Mori, S. and Obata, H.: On the degradation of electron microscopical melanin granules of epidermis. Jap. J. Berm., Ser. B, 77: 337, Mishima, Y.: Cellular and subcellular activities in the nevocytic and melanocytic melanomas, p. 509, Advances in Biology of Skin, Vol. 8. Ed., Montagna, W., Pergamon Press, Oxford, Luft, J. H.: Improvements in epoxy resin embedding methods. J. Biophys. Biochem. Cytol., 9: 409, Reynolds, E. S.: The use of lead citrate at high ph as an electron-opaque stain in electron microscopy. J. Cell Biol., 17: 208, Majno, G.: Ultrastructure of the vascular membrane, p. 2293, Handbook of Physiology, Sec. 2, Vol. 3. American Physiological Association, Waslungton, Cotran, R. S.: Endothelial phagocytosis: An electron microscopic study. Exp. Molec. Path., 4: 217, Hashimoto, K., Gross, B. G. and Lever, W. F.: Angicma corporis diffusum (Fabry). Histochemical and electron microscopic studies of the skin. J. Invest. Berm., 44: 119, Sagebiel, R. W. and Parker, F.: Electron microscopic observations relating Fabry's disease to other sphingolipoidosis. Clin. Res., 14: 273, Sagebiel, R. W. and Parker, F.: Cutaneous lesions of Fabry's disease: glyeolipid lipoidosis. J. Invest. Berm., 50: 208, Zelickson, A. S.: Skin pigmentation and chlorpromazine. J.A.M.A., 194: 670, Movat, H. Z. and Fernando, N. V. F.: The fine structure of the terminal vascular bed. 5. The venules and their perivaseular cells (Pericytes, adventitial cells). Exp. Molec. Path., 3: 98, Cotran, R. S., Gattuta, M. L. and Majno, 0.: Studies on inflammation. Fate of intramural vascular deposits induced by histamin. Amer. J. Path., 47: 1045, 1965.