Epstein-Barr virus-associated intrahepatic cholangiocarcinoma: a diverse morphological spectrum that correlates with patient prognosis.

Epstein-Barr virus (EBV)-associated intrahepatic cholangiocarcinoma (EBVaICC) is a rare condition with limited comprehensive descriptions of its clinicopathological features. This study investigated the wide morphological spectrum of EBVaICC to improve diagnostic accuracy and explored the associations between morphological characteristics and prognosis. Nineteen cases of EBVaICC were retrospectively analysed, and 102 cases reported in the literature were reviewed. Four patients were male, and 15 were female. The median age of the patients was 56 years (range 37-78 years). The median size of the tumours was 4.5 cm (range 1.3-14.0 cm), and 13 patients (68.4%) presented with a single tumour, while six (31.6%) exhibited multiple hepatic lesions. Tumours were assessed for various histological features and assigned to the following morphological groups: duct (31.6%, 6/19), lymphoepithelioma-like (15.8%, 3/19), anaplastic (26.3%, 5/19), and mixed subtypes (26.3%, 5/19). The duct subtype exhibited a variety of tubular formations with low-grade nuclear atypia and few mitoses [<5/10 high-power fields (HPFs)], mimicking well-differentiated cholangiocarcinoma within a background of dense lymphoplasmacytic infiltration. The lymphoepithelioma-like subtype featured vesicular nuclei with indistinct cell boundaries, cohesive arrangements, and characteristic lymphoepithelial lesions. The anaplastic subtype was characterised by a nest-like or solid growth pattern with high-grade nuclear atypia with abundant mitoses (≥10/10 HPF), ​yet lacked abundant lymphoplasmacytic infiltration. Immunohistochemically, the neoplastic cells stained positive for biliary markers (CK7 and CK19) and were 100% positive for EBV-encoded RNA. Six anaplastic cases (including one case of mixed subtype) were categorised into group A, and the other 13 cases were classified as group B. The follow-up assessment revealed significantly lower 2-year progression-free survival (0% vs 81.5%) and overall survival (0% vs 100%) rates in patients in group A than in group B (p<0.05). EBVaICC presents a diverse morphological spectrum and correlates with the patient prognosis. Recognising these morphological variations, especially the anaplastic subtype, is essential for accurate diagnosis, prognostic assessment, and personalised management.