Experiments were performed to study the earliest changes and their sequence in the development of malignant
tumors following implantation of 10 mg of
nickel subsulfide (Ni3S2) into the right quadriceps muscle of seven male Fischer rats. Biopsies were performed when nodules reached one to three mm, and, later, when they were five to seven mm, and, finally, at sacrifice, to confirm the fully developed
tumor pattern. Light microscopy of the earliest samples showed groups of cells clumped and scattered among degenerating muscle fibers. Mitoses were seen and inflammatory cells were not a feature. Electron microscopy showed individual degenerating muscle fibers, but also cells with characteristic features of myofibroblasts. In many cells
osmium, dense fragments suggestive of crystalline material, were seen in the cytoplasm and nuclei. In the second set of biopsy material, myofibroblasts with well defined and dilated rough endoplasmic reticulum, intracellular membrane-bound
collagen, and microfilaments with focal "dense bodies" were numerous. Mitoses were frequent. Immunohistochemistry showed strongly positive reaction to
Vimentin and muscle-specific Actin in the
tumor cells. In the fully developed
tumors, the previously described typical storiform cell pattern with spindle and spheroidal cells with frequent mitoses was seen.
Vimentin and muscle-specific Actin stains were strongly positive. The long latent period, the evidence of cell degeneration,
necrosis, foreign material (probably of
nickel composition), cell invasion, and subsequent rapid myofibroblast-type cell development, proliferating to malignant
tumors highly suggestive of
malignant fibrous histiocytoma, seem to suggest an epigenetic form of carcinogenicity of cytotoxic variety. Whether the
tumor cells derive from transformed myofibrils or from activated pluripotential mesenchymal cells, or from both, remains in doubt.