• cancer initiating cell;
  • CD44;
  • lung cancer;
  • p63;
  • podoplanin;
  • squamous cell carcinoma

Cancer-initiating cell (CIC) hypothesis suggests that CICs may be responsible for the generation of tumors that recapitulate the histology of the primary tumor at distant sites. We investigated the distribution of CIC markers (podoplanin (PDPN), CD44, and p63) positive cells of lung squamous cell carcinoma (SqCC) within primary and matched lymph node (LN) metastatic tumors to confirm this hypothesis (n = 113). In 61 cases, the PDPN-positive cells were localized in more peripheral areas of the tumor nests than the CD44- and p63-positive cells. This distribution pattern corresponded to a ‘hierarchical distribution (HD)’ reported previously. Among the cases with HD-(+) primary tumors (n = 61), the number showing HD-(+) LN metastatic tumors was 31 (51%), while among the cases with HD-(−) primary tumors (n = 52), the number showing HD-(+) LN metastatic tumors was 7 (13%) (p < 0.01). Primary and matched pulmonary metastatic (PM) tumors were also analyzed (n = 31), and a significant relationship of the HD pattern between them was also detected (p = 0.01). These results indicate that PDPN-positive cells might reflect the most immature cells in the differentiation process of metastatic SqCC and might generate metastatic tumors that recapitulate the histologic heterogeneity of the primary tumor.