Risk of Hepatocellular Carcinoma in Subcentimeter Liver Nodules Identified on Surveillance Ultrasound: A Systematic Review

Background & Aims: Guidelines recommend that sub-centimeter nodules on ultrasound be followed with short-interval surveillance ultrasound, given assumed low risk of hepatocellular carcinoma (HCC) and suboptimal diagnostic imaging performance in lesions <1 cm. We performed a systematic review to estimate HCC risk among patients with cirrhosis and sub-centimeter nodules detected on ultrasound. Methods: We systematically searched Ovid MEDLINE and EMBASE databases for relevant articles published between January 2005 and July 2024. A random-effects model was used to calculate the pooled proportion of incident HCC. Results: We identified 9 eligible studies, of which 5 provided both lesion- and patient-level data (n = 354 patients), 2 patient-level alone (n = 888 patients), and 2 lesion-level alone (n = 69 lesions). The pooled proportion of incident HCC was 31.9% (95% confidence interval [CI], 8.7%–69.7%) on a lesion-level and 21.3% (95% CI, 6.0%–53.6%) on a patient-level; however, pooled estimates were limited by high heterogeneity (I² >90%). Among 2 studies with study periods post-dating 2015, HCC developed in only ∼5% of patients during a median follow-up of 2 years. Risk factors associated with incident HCC were older age, male sex, elevated alpha-fetoprotein levels, thrombocytopenia, and Child Pugh B cirrhosis. Limitations of studies included small sample sizes, selection bias, ascertainment bias for HCC, and failure to report factors associated with HCC. Conclusion: Up to one-fifth of patients with sub-centimeter nodules may develop HCC, although contemporary cohorts report a substantially lower risk. Older patients and those with elevated alpha-fetoprotein levels or poorer liver function are at greatest risk of HCC, highlighting an unmet need for better risk stratification models.