Autophagy in endometrial carcinomas and prognostic relevance of 'stone-like' structures (SLS): What is destined for the atypical endometrial hyperplasia?

Autophagy, as an intracellular adaptation mechanism for oxygen and nutrient deprivation, is associated with tumor cell survival and aggressiveness. This was reaffirmed in a series of 360 endometrial carcinomas, using a standard immunohistochemical technique and the LC3A antibody, capable of recognizing both the soluble (LC3A-I) and the membrane-bound form (LC3A-II) of the protein. LC3A reactivity was recognized in three basic patterns-diffuse cytoplasmic, cytoplasmic/juxta-nuclear, and the so-called "stone-like" structures (SLS). The latter has emerged as the hallmark of autophagic activity, being detected exclusively in endometrial carcinomas and their immediate precursor lesions, namely the atypical hyperplasias, albeit in small numbers. Other forms of hyperplasia without cytological atypia and normal endometrial tissues expressed only cytoplasmic staining patterns. High SLS counts, presumed to reflect excessive levels of autophagic activity, were associated with tumors of extremely poor prognosis. In contrast, a basal level of autophagic activity, as exemplified by the diffuse cytoplasmic and the cytoplasmic/juxta-nuclear patterns, had no impact on prognosis. Survival, according to tumor cell types, showed that serous papillary, clear cell and the high-grade endometrioid carcinomas had the worst prognosis compared to low-grade endometrioid carcinomas, but interestingly, within this tumor group, those having high-SLS counts had a much worse survival rate than those that did not. It is concluded that an assessment of autophagic activity, particularly in the form of SLS, is useful for evaluating tumor aggressiveness and, in the absence or an excess of SLS, it may also prove valid for differentiating grade 1 endometrioid adenocarcinomas from their precursor lesions.