The stone-like pattern of autophagy in human epithelial tumors and tumor-like lesions An approach to the clinical outcome

Cancer cells survive the adverse conditions of the extracellular milieu, i.e., hypoxia and nutrient deprivation, through angiogenesis and anaerobic glycolysis. Yet, continuously proliferating malignant cells, having high metabolic needs, may not be fully covered by these processes and seek additional sources of energy. An alternative metabolic pathway for providing energy in tumor cells is autophagy-a self-degradation mechanism by which cells recycle their own cytoplasmic constituents. Given that the clinical impact of this phenomenon on human malignancies remains by and large unexplored, we investigated morphological patterns of autophagy primarily in breast carcinomas and, subsequently, in a series of other epithelial tumors and tumor-like lesions from various organs and cell types. The microtubule-associated protein 1 light chain 3A (MAP1-LC3A) antibody and a standard immunohistochemical technique were used. Three main patterns of autophagic activity were recognized: diffuse cytoplasmic, cytoplasmic/juxta-nuclear and stone-like structures (SLS); the latter are dense, spheroidal, amorphous structures, of 5 mu m average size, typically enclosed within cytosolic vacuoles. Normal tissues, in the proximity of malignant tumors, and tumor-like lesions expressed with remarkable consistency the cytoplasmic and the juxta-nuclear pattern, but were deprived of SLS. Interestingly, tumors having a substantial number of SLS were of high grade and unfavorable prognosis, whereas those with juxta-nuclear accumulation of LC3A protein were associated with an improved survival. Prognosis was unaffected by the diffuse cytoplasmic pattern. It is concluded that immunohistochemical staining for LC3A is a suitable method for detecting autophagy in human tissues by light microscopy, but the significance of the various patterns described needs further evaluation.