FAPα-positive fibroblasts in expert-reviewed colorectal hyperplastic polyps identify patients at increased risk of metachronous adenoma: a retrospective cohort study

Aims: Serrated lesions contribute substantially to colorectal cancer (CRC), while routine management of small distal hyperplastic polyps (HPs) assumes low risk. Surveillance guidelines nevertheless incorporate uncertainty at the HP/SSL interface and recommend shortened intervals for large serrated lesions. We tested whether fibroblast activation protein-alpha; (FAPalpha) expression by stromal fibroblasts within expert-reviewed HPs stratifies risk of subsequent neoplasia. Methods and results: In a single centre historical cohort, FAPalpha; immunohistochemistry (Abcam ab53066, 1:200) was performed on FFPE colon tissues from 64 patients (normal colon n=10; HP n=39; low grade TA n=6; high-grade TA n=4; adenocarcinoma n=5). FAPalpha positive stromal fibroblasts were quantified in 20 randomly selected fields at magnification 1000 by two blinded readers (ICC 0.93). Among 39 patients with expert reviewed index HPs and colonoscopic follow up, the endpoint was metachronous adenoma occurring in the same general colonic area as the index HP, with proximal defined as ascending colon and distal as descending colon. Follow-up colonoscopies were scheduled every 2 years for up to 10 years. ROC analysis identified an optimal threshold of [≥]9 FAPalpha positive fibroblasts (AUC 0.8658; sensitivity 81.25%, specificity 87.93%). FAPalpha high status (44% of HPs) was associated with shortened neoplasm free survival (log-rank p=0.0012): five-year neoplasm free survival 41% versus 91% for FAPalpha; no/low. In multivariable Cox modelling, FAPalpha high status remained independently associated with metachronous adenoma (HR 4.5, 95% CI 1.2-16.8, p=0.022). Conclusion: FAPalpha+ fibroblasts in expert-reviewed colorectal HPs identify a high-risk subgroup for metachronous adenoma, supporting stromal activation markers as a feasible pathology-anchored stratification tool.