The analysis of the distribution of genetic alterations in tumor-independent, tumor-associated ESD and ESCC allowed for the proposal of a two-hit event to explain ESCC development based on precursor lesions: the loss of heterozygosity or mutations in TP53 occurs early (being detectable in a part of tumor-independent ESD), but the subsequent development of ESCC requires the full inactivation of TP53 [11]. Here, TP53 is linked to neoplasm.