Atypical Ductular Reactions Are a Distinct Regenerative Phenomenon in Patients With Hepatocellular Carcinoma (HCC) After Transarterial Chemoembolization.

Transarterial chemoembolization (TACE) is increasingly used in patients with hepatocellular carcinoma (HCC), the most frequent primary liver tumor. Atypical ductular reactions (aDRs) challenge the histological diagnosis in specimens of patients after embolization treatment, mimicking intrahepatic cholangiocarcinoma (CCA) or combined hepatocellular carcinoma-cholangiocarcinoma (HCC-CCA). We characterized aDRs in patients with HCC after embolization treatment in association with therapy mode, response, and survival using histomorphology and spatial microdissection. This retrospective, single-center, longitudinal cohort study included 188 patients with HCC. We compared a study group (n = 105 patients with a total of 206 tumor nodules) vs a treatment-naïve control group (n = 83/112 nodules). The presence of embolization compounds, the type of embolization treatment, tumor necrosis, morphology, and the expression of biliary markers (CK7/19, SOX9) were assessed on whole slides and a tissue microarray using machine-learning-assisted marker profiling. Spatial microdissection and sequencing with the Oncomine Comprehensive Assay (version 3) tested genetic landscapes. The relative risk for aDRs was increased in patients with HCC following embolization therapy compared with the control group (relative risk, 3.6; P < .05). Morphology appears as ribbon-like with atypical, confluent ducts usually found on the interface of necrosis and vital tumor nodules. Strong intensity of CK7/19 and SOX9 was observed throughout, compared with a heterogenous expression pattern in combined HCC-CCA. Spatial microdissection of aDRs showed variants of unknown significance in 1 of 13 cases (NTRK3) but no CCA-typical mutations. In contrast, combined HCC-CCA (n = 4) displayed oncogene alterations in known targets (TP53, BAP1, and TERT). Increased aDRs in specimens of patients with HCC after transarterial embolization treatment can be identified as regenerative phenomenon with distinct morphology and immunophenotype.