Shadow Cell Differentiation: A Comparative Analysis of Modes of Cell Death with Apoptosis and Epidermal/Trichilemmal Keratinization

Abstract

Shadow cells are characterized by an eosinophilic cytoplasm and a ghost-like nuclear contour; the cell shape is preserved, in spite of nuclear disappearance. Shadow cell nests (SCNs) are frequently observed in pilomatricoma (PMX), where the transitional cells immediately adja- cent to SCNs often have a crescent-shaped nucleus showing fragmentation similar to that of apoptotic bodies. They show nuclear accumulation of beta-catenin and DNA double strand breaks (as revealed by in situ 3′-tailing reaction or immunohistochemistry for single-stranded DNA [ssDNA]), while they are negative for cleaved caspase-3 or cleaved lamin A, suggesting that shadow cell differentiation (SCD) is a caspase-independent programmed cell death. SCD can be differentiated from epidermal keratinization (EK) and trichilemmal keratinization (TK) based on the expression pattern of beta-catenin, ssDNA, and caspase-14/CD138. SCD is ob- served not only in PMX, but also sometimes in basal cell carcinomas, gonadal teratomas, and various extra-cutaneous carcinomas. In particular, SCNs are found in 24% of endometrial ad- enoacanthoma and are derived from squamoid morules. This establishes a link between ba- saloid cells in PMX and squamoid morules in endometrial adenoacanthomas as common pre- cursors of shadow cells. Overall, it is suggested that SCD is different from, but partly similar to, apoptosis and that SCD and EK/TK should be differentiated from the standpoint of cell death/differentiation.