"Thanatosomes": a unifying morphogenetic concept for tumor hyaline globules related to apoptosis

Hyaline globules (HG) have been observed in a large variety of unrelated categories of tumors and benign tissues. Different explanations for their formation have been proposed, varying according to tumor type and anatomic location. We have studied 80 tumor cases containing HG, by light microscopy, electron microscopy, immunohistochemical stains for various plasma proteins, and in situ DNA-end labeling for apoptosis. On light microscopy, HG were invariably related to areas of increased apoptosis and often contained apoptotic nuclear fragments. The HG stained as expected, with variable intensity with acidic stains. Most cells containing HG stained with immunohistochemical stains for all plasma proteins examined (alpha-1-antitrypsin, ferritin, C3, kappa and lambda light chains, and IgG), indicating an increased plasma membrane permeability. A morphologic change associated with the increased permeability was cytoplasmic blebbing. In the HG themselves, immunohistochemical stains for the plasma proteins were either diffusely positive or stained only the periphery of the larger HG. Double stains for apoptosis and plasma proteins confirmed the increased plasma membrane permeability to proteins of apoptotic cells in general and cells containing HG in particular. Free hyaline globules were often linked to the extracellular matrix by fibrin fibrils. Ultrastructurally, the HG appeared as phagosomes/secondary lysosomes or areas of cytoplasmic condensation surrounded by rough endoplasmic reticulum whorls. These were always associated with intense cytoplasmic blebbing. We conclude that HG reflect stages of cell injury, which in most instances relate to apoptotic cell death. They are specifically associated with the cytoplasmic blebbing and condensation typically seen in this form of cell death. These phenomena are accompanied by plasma protein influx (insudated plasma) and formation of distinct intracellular "hyalinized" cellular fragments. With cell fragmentation, the HG become extracellular and are likely to be ultimately disposed of by a process of "remodeling" and incorporation into the extracellular matrix, followed by collagenization. The latter process partly occurs by the initial linking of all components (HG, collagen fibers, cellular fragments, etc.) by a network of fibrin. The process of formation of HG follows a stereotypical pathway independent of cell type. Because it results mostly from apoptotic cell death, it is more pronounced in rapidly growing tumors or posttreatment. We propose the term thanatosomes for the entire spectrum of HG to emphasize their relationship to cell death. HUM PATHOL 31:1455-1465.