Borderline Hepatocellular Adenomas: a Practical Diagnostic Approach Based on Pathological and Molecular Features.

Borderline hepatocellular adenomas (BL-HCA) are characterized by focal architectural/cytological atypia and reticulin loss, features that are insufficient for a definitive diagnosis of hepatocellular carcinoma (HCC). The diagnosis and management of BL-HCA are challenging as their biological behavior, especially in terms of malignant potential, is still debated. We aimed to compare the clinicopathological and molecular features of BL-HCA with those of typical HCA (T-HCA), HCA with malignant transformation (HCC on HCA), and HCC to assess the risk of malignancy. One hundred and six liver resection specimens were retrospectively selected from two reference centers, including 39 BL-HCA, 42 T-HCA, 12 HCC on HCA, and 13 HCC. Somatic mutations, including TERT promoter mutations associated with HCA malignant transformation, and the gene expression levels of 96 genes were investigated in 93 frozen samples. Additionally, TERT promoter mutations were investigated in 44 formalin-fixed, paraffin-embedded samples. The clinical features of patients with BL-HCA were similar to those of patients with T-HCA, patients being mainly women (69%) with a median age of 37 years. The median tumor size was 7.5 cm, 64% of patients had a single nodule, and no recurrence was observed. Compared to T-HCA, BL-HCA were significantly enriched in β-catenin mutated HCA in exon 3 (41% vs. 6%, p<0.001). Unsupervised statistical analysis based on gene expression showed that BL-HCA overlapped with T-HCA and HCC on HCA, favoring a molecular continuum of the tumors. TERT promoter mutations were observed only in HCC on HCA (42%) and in HCC (38%). In conclusion, these results suggest that despite their worrisome morphological features, the clinicopathological and molecular features of BL-HCA are much closer to those of T-HCA than HCC on HCA or HCC. This strongly supports the usefulness of combining morphological and molecular analyses in a practical diagnostic approach for guiding the management of BL-HCA.