Differential diagnosis of small hepatocellular nodules in cirrhosis: surrogate histological criteria of TERT promoter mutations

Aims The differential diagnosis of small hepatocellular nodules in cirrhosis between dysplastic nodules and hepatocellular carcinoma (HCC) remains challenging on biopsy. As TERT promoter (p TERT ) mutations may indicate the nodules already engaged in the malignant process, the aim of this study was to identify histological criteria associated with p TERT mutations by detecting these mutations by ddPCR in small formalin‐fixed paraffin‐embedded (FFPE) hepatocellular nodules arising in cirrhosis. Methods and results We built a bicentric cohort data set of 339 hepatocellular nodules < 2 cm from cirrhotic samples, divided into a test cohort of 299 resected samples and a validation cohort of 40 biopsies. Pathological review, based on the evaluation of 14 histological criteria, classified all nodules. p TERT mutations were identified by ddPCR in FFPE samples. Among the 339 nodules, ddPCR revealed p TERT mutations in 105 cases (31%), including 90 and 15 cases in the test and validation cohorts, respectively. On multivariate analysis, three histological criteria were associated with p TERT mutations in the test cohort: increased cell density ( P = 0.003), stromal invasion ( P = 0.036) and plate‐thickening anomalies ( P < 0.001). With the combination of at least two of these major criteria, the AUC for predicting p TERT mutations was 0.84 in the test cohort (sensitivity: 86%, specificity: 83%) and 0.81 in the validation cohort (sensitivity: 87%, specificity: 76%). Conclusions We identified three histological criteria as surrogate markers of p TERT mutations that may be used in routine biopsy to more clearly classify small hepatocellular nodules arising in cirrhosis.