Abstract
Purpose: :
Melanoma-associated retinopathy (MAR), induced by cutaneous or uveal melanomas, results from the cross-reaction of tumor-directed autoantibodies with retinal antigens, which destroy retinal tissue. MAR ultrastructural descriptions and autoantibody localization are lacking. We present for the first time ocular ultrastructure and the retinal targets of the autoantibodies of MAR.
Methods: :
A pair of autopsied eyes of an 80 year-old male with metastatic cutaneous melanoma and positive retinal autoantibodies was examined with histopathology including transmission electron microscopy, and immunohistochemistry (Calbindin, calcium binding proteins; PKCalpha, protein kinas C; and TRPM1, a mGluR6-coupled cation channel in ON bipolar cells) using avidin-biotin-complex immunohistochemistry.
Results: :
The outer plexiform layer (OPL) was the most affected retinal tissue in both eyes; it showed thinning and atrophy, which extended to both the outer (ONL) and inner (INL) nuclear layers, resulting in focal degeneration, edema, and atrophy. The retinal lesions were mostly from OPL toward the INL. No active inflammation or melanoma cells were observed. Ultrastructural damages within the outer plexiform layer included extensive homogenous deterioration of the synapses characterized by numerous empty vacuoles, disintegrated mitochondria with fragmented inner membrane, disorganization and stacking of filaments, and numerous apoptotic bodies. The adjacent cells in the INL and ONL showed various degrees of cytoplasmic breakdown. Aberrant immuno-reactivities illustrated blurred condensed bipolar dendritic structure (TRPM1), tightly packed INL (PKC), and loss of ONL (calbindin), which suggested abnormal TRPM1 cation channels of retinal ON bipolar cells.
Conclusions: :
Ultrastructure and immunohistochemistry of the autopsied eyes with MAR provided the first structural evidence of targeting the OPL, ONL and INL. MAR-autoantibodies attacking channels in the dendritic terminals of ON bipolar cells and resulting abnormal synaptic transmission are possibly the main mechanism for MAR retinopathy.
Keywords: melanoma • autoimmune disease • retinal degenerations: cell biology