Yutaka Mishima

Melanocytic and nevocytic malignant melanomas. Cellular and subcellular differentiation

Two biologically and clinically different malignant melanomas are found in man. As compared to the malignant melanoma developed from junction nevus, the melanoma developed from Dubreuilhs precancerous melanosis has a slower rate of growth, metastasis and invasiveness. Furthermore, in contrast to melanoma of junction nevus origin, melanoma from Dubreuilhs melanosis is radiosensitive and does not assume the amelanotic form. Not only the malignant melanomas but also the premalignant stages exhibit differences. Dubreuilhs precancerous melanosis, in contrast to junction nevus, is a condition which occurs during later life in exposed areas, is radiosensitive and has a high incidence of malignant transformation. Cellular and subcellular differential characteristics expressing enzymic and ontogenic differences of these two melanomas are described. The author proposes that in the future we consider human malignant melanoma to be not one but two diseases—melanocytic malignant melanoma and nevocytic malignant melanoma. These may be called malignant melanocytoma and malignant nevocytoma, respectively.

Intracellular localization of tyrosinase inhibitor in amelanotic and melanotic malignant melanoma.

Summary.— Intracellular distribution of the tyrosinase inhibitor in malignant melanoma cells has been investigated in order to elucidate the defect of melanization in the pigment cell cytoplasm and premelanosomes of amelanotic melanoma. We have found that the tyrosinase inhibitor has its highest activity in the cytoplasmic soluble fraction for both amelanotic and melanotic melanomata. However, inhibitor assay of melanoma subfractions reveals a distinct difference between the inhibitor activity of amelanotic and melanotic melanomata. Premelanosome‐containing subfractions of amelanotic melanomata contain much higher inhibitor activity than those of melanotic malignant melanomata. A high concentration of inhibitor seen in subfraction 3 which contains most of the total succinoxidase activity is found to be contained in the premelanosomes of this subfraction.

ELECTRON MICROSCOPY OF HUMAN CUTANEOUS NERVE PIGMENTATION

IN 1912 Weidenreich deseribed specific pigment zoneB around nerve fibres in the ocular fuiidus, olfactory epithelium and around the brain and spinal cord under the name perineurale PigmenthilUe. Later the inten-elatiousliip of pigmentation and neural elements was successfully demonstrated in ampiiibia, (ish, and reptiles by ligation and electrical stimulation resulting in integumental colour ehange (Abramowitz, 1936). Since then there has been much speculation and investigation which, however, have failed to demonstrate a direct relationship between nerve and pigment cells in human skin (Lerner et al., i U6(i), although the presence of pigmented cells closely associated with cutaneous sensory and autonomic nerves has been demonstrated (Kawamurae(«/.. 1964). The formation of melanocytes and naevus cells from neural crest derivatives is generally accepted. The question of whether intraeutaneous naevus cells may be directly derived from Schwann cells of nerves in the adult skin (Masson, 1951; Winkelmann, 1963) is still debated. One approaeh to demonstrating a relationship between naevus cells and neiu-al elements was based on the existence of the perineurale PigmentMlle (Ito, 1952a). The exact nature, however, of these perineurial pigment zones in human skin has remained undetermined, liefore electron microscopic investigation the presence of pigment around nerve fibres could be explained in the following ways, (i) The presence of melanized melanocytes around the nerve fibre which may or may not be derived from inactive melanocytes. (ii) The transformation of Schwann cells into melanocytes. {iii) The presence of melanophages along the nerve fibre, (iv) The jihagocytosis of melanosomes by Sehwann cells or other neural structures.

Electron microscopy of micro‐focal necrosis in malignant melanomas

Malignant melanoma often undergoes spontaneous focal necrosis and ulceration. In conjunction with this gross and microscopic necrosis there appears a wide spectrum of subcellular changes, accompanied by hydrolytic enzyme activity in the cytoplasm of malignant melanoma cells. In die present study, these subcellular changes are described and differentiated from die accelerated subcellular melanogenic activity also occurring in the malignant melanoma cell. Three types of Fortners hamster melanoma, whose ontogenies include focal necrotic changes like those of their human counterparts, have been investigated electron microscopically and histochemically. The electron microscopic acid phosphatase reaction confirms that the hydrolytic activity occurring in malignant cells of both melanotic and amelanotic melanoma is localized within autophagic vacuoles which are thus shown to be lysosomes. Electron microscopy reveals that the occurrence of microfocal degradation by the segregation of ergastoplasm and mitochondria within lysosomes is closely related to the spontaneous necrosis seen in malignant melanomas. This lysosomal engulfment is also involved in the segregation and degradation of premelanosomes and melanosomes. Increased tyrosinase activity and melanosome production characteristic of malignant melanoma cells proceed concomitantly with the appearance of lysosome formation and hydrolytic activity until the melanoma cells complete their own ontogeny and the ontogeny of the melanosomes which they have synthesized.

Cholinesterase and tyrosinase activity in malignant melanoma

A series of human amelanotic and melanotic melanomas derived from both junction nevus and Dubreuilhs precancerous melanosis has been studied to investigate further the physiologic and cytopathogenic significance of cholinesterase in relation to the tyrosinase activity of these tumors. Cholinesterase activity has been found to be sharply localized in malignant melanoma of primary as well as metastatic lesions of the skin and viscera. It is evident that cholinesterase activity can exist concomitantly with tyrosinase activity in the cytoplasm of melanosome synthesizing melanoma cells.

Chemical Modeling with p-Boronophenylalanine for Boron Accumulation to and Release from Melanoma

This paper describes a proposed mechanism of boron accumulation to and release from melanoma after administration of p-Boronophenylalanine (p-BPA) to melanoma patients. The study is based on chemical experiments modeling the phenomena occurring in melanoma cells. Before the mechanism study, we would like to mention the history of the BNCT compound, p-BPA.

Subcellular tyrosinase activity in Fortner's malignant melanoma.

SUMMARY. —Biochemical and macromolecular characterizations of Fortners melanotic melanoma of Syrian (golden) hamsters and of B‐16 melanotic mouse melanoma were made using the Warburg manometric technique for estimation of the subcellular distribution of tyrosinase activity.

Two Cases of Primary Malignant Melanoma Treated by Selective Melanoma Thermal Neutron Capture Therapy

In 1972, the study of Selective Melanoma Thermal Neutron Capture Therapy (Selective-Melanoma NCT) was initiated by Mishima’s group1). In order to apply the theory that reaction products between 10B and neutrons can destroy cells containing 10B 2), 10B had to be transported into malignant melanoma (Mm) cells. For that purpose, 10B1-para-borono-phenylalanine (10B1-BPA) was synthesized. It is a precursor dopa analogue and accumulates in melanosomes within Mm cells (Fig 1) 3,4). 10B1-BPA was complexed with fructose so that it could be soluble at pH near 7.4 (almost equal to blood pH) and be suitable for Selective-Melanoma NCT 5). The first clinical application to metastatic Mm was performed successfully in 1987 1, 6–8). Since then 16 cases of Mm have been treated. Here we report a case of lentigo maligna melanoma on the right face and a case of acral lentiginous melanoma on the right sole, treated by Selective-Melanoma NCT.