SEPT9 Expression in Hepatic Nodules: An Immunohistochemical Study of Hepatocellular Neoplasm and Metastasis

The methylated SEPT9 DNA (mSEPT9) in plasma is a US Food and Drug Administration (FDA)-approved screening biomarker in colorectal cancer and is emerging as a promising diagnostic and prognostic biomarker in hepatocellular carcinoma (HCC). We evaluated the SEPT9 protein expression by immunohistochemistry (IHC) in various hepatic tumors from 164 hepatectomies and explants. Cases diagnosed as HCC (n=68), hepatocellular adenoma (n=31), dysplastic nodule (n=24), and metastasis (n=41) were retrieved. SEPT9 stain was performed on representative tissue blocks showing tumor/liver interface. For HCC, archived IHC (SATB2, CK19, CDX2, CK20, and CDH17) slides were also reviewed. The findings were correlated with demographics, risk factors, tumor size, alpha fetoprotein levels at diagnosis, T stage and oncologic outcomes, with significance defined as P<0.05. Percentage of SEPT9 positivity differed significantly among hepatocellular adenoma (3%), dysplastic nodule (0%), HCC (32%), and metastasis (83%, P<0.001). Compared with patients with SEPT9- HCC, those with SEPT9+ HCC were older (70 vs. 63 y, P=0.01). The extent of SEPT9 staining correlated with age (r(s)=0.31, P=0.01), tumor grade (r(s)=0.30, P=0.01), and extent of SATB2 staining (r(s)=0.28, P=0.02). No associations were found between SEPT9 staining and tumor size, T stage, risk factors, CK19, CDX2, CK20, or CDH17 expression, alpha fetoprotein levels at diagnosis, METAVIR fibrosis stage, and oncologic outcome in the HCC cohort. SEPT9 is likely implicated in liver carcinogenesis in a HCC subset. Similar to mSEPT9 DNA measurement in liquid biopsies, SEPT9 staining by IHC may prove helpful as an adjunct diagnostic biomarker with potential prognostic ramifications.