SARIFA Is Associated with Lymph Node Metastases in PT3 and PT4 Gastric Cancers

<b>Background/Objectives</b>: Advanced gastric cancer usually has an unfavorable prognosis. Stroma AReactive Invasion Front Area (SARIFA) is a newly recognized biomarker of aggressiveness, easily recognized as five tumor cells in direct contact with adipocytes in perigastric, submucosal, and perivascular adipose tissue. We investigated this phenomenon and correlated it with other pathohistological variables. <b>Material and Methods</b>: The sample includes 102 Croatian patients with locally advanced gastric cancer, who underwent total gastrectomy/lymphadenectomy between 2012-2018 and in 2023 at University Hospital Split, Croatia, and had pathological stage pT3 or pT4. Representative histological specimens were analyzed for SARIFA, and results were compared with other variables and overall survival. External validation and gene expression analysis of CD36 and FABP4 were performed using the TCGA-STAD cohort. <b>Results</b>: SARIFA was significantly associated with positive pN status (<i>p</i> = 0.009) and perineural invasion (<i>p</i> = 0.043). Patients with SARIFA had a more than fivefold increased risk of nodal involvement (OR = 6.35; 95% CI: 1.35-29.84; <i>p</i> = 0.019). Lymphovascular invasion (LVI) was associated with nodal disease (OR = 4.39; 95% CI: 1.194-16.143; <i>p</i> = 0.026), and SARIFA was marginally associated (OR = 4.886; 95% CI: 0.985-24.241; <i>p</i> = 0.052). Patients who had both LVI and SARIFA had a higher proportion of affected lymph nodes (<i>p</i> = 0.009). SARIFA status did not significantly affect overall survival. Gene expression analysis showed a significant increase in CD36 expression, while FABP4 expression was elevated but not statistically significant, in SARIFA-positive cases. <b>Conclusions</b>: SARIFA could be used as a marker for invasiveness and further investigated due to its predictive potential.