S100‐stained perineural invasion is associated with worse prognosis in stage I/II colorectal cancer: Its possible association with immunosuppression in the tumor

Perineural invasion (PNI) is known as a poor prognostic factor in colorectal cancer (CRC). Although histopathological evaluation of PNI is usually conducted on hematoxylin and eosin (HE)-stained sections (HE-PNI), it remains controversial whether PNI can be precisely evaluated only by HE-staining, and its concise mechanisms causing worse prognosis remains elusive. In this study, we examined the impact of PNI evaluated by S-100-immunostaining (S100-PNI) on postoperative mortality in 279 consecutive CRC patients and further investigated its association with the tumor immune microenvironment. S100-PNI was present in 67.3% of tumors whereas HE-PNI was present in 18.5%. A 5-year cumulative incidence of death in the S100-PNI-positive group was significantly higher than that in the S100-PNI-negative group. Further statistical analyses revealed that S100-PNI was an independent prognostic factor of all-cause mortality in stage I/II but not in stage III/IV. Importantly, S100-PNI was associated with the altered tumor immune microenvironment. Infiltrating immune cell profiling revealed that stromal lymphocytic reaction, which was inversely correlated with postoperative mortality, was significantly reduced in S100-PNI-positive tumors compared to S100-PNI-negative tumors in stage I/II. These results indicated that S100-PNI was a poor prognostic factor in stage I/II CRC with possible association with immunosuppression in the tumor.