In an exploratory survival analysis among patients with iCCA (n = 25), those with above-median CD9<sup>+</sup>CD133/2<sup>+</sup> EV levels (n = 13) had shorter overall survival (median 91 vs. 389 days; HR: 2.80, 95% CI: 1.16-6.74; p = 0.005).<h4>Conclusions</h4>Integrated EV and serological profiling could enable minimally invasive differentiation between HCC and iCCA within LR-M lesions. The gene discussed is PROM1; the disease is hepatocellular carcinoma.