Clinicopathologic spectrum and diagnostic strategies of intrahepatic neoplasms with prominent inflammatory background.

Intrahepatic neoplastic lesions with prominent inflammatory background (HNLwPIBs) constitute a heterogeneous group of entities that frequently pose substantial diagnostic challenges because of overlapping morphological features. To characterize their clinicopathological spectrum, diagnostic pitfalls, and key distinguishing clues, we retrospectively analyzed 60 cases of HNLwPIBs diagnosed at our institution over a 11-year period (2015-2025). The cohort comprised 8 distinct entities, including lymphoepithelioma-like cholangiocarcinoma (LEL-ICC), lymphocyte-rich hepatocellular carcinoma (LR-HCC), inflammatory angiomyolipoma (IAML), inflammatory pseudotumor (IPT) versus inflammatory myofibroblastic tumor (IMT), EBV-positive inflammatory follicular dendritic cell sarcoma (EBV+IFDCS), EBV-positive diffuse large B-cell lymphoma (EBV+DLBCL), pseudolymphoma (PL), and mucosa-associated lymphoid tissue extranodal marginal zone B-cell lymphoma (MALT lymphoma). Each entity showed characteristic morphologic and immunophenotypic features that supported accurate classification when systematically integrated. Several diagnostically challenging patterns were identified. One case of LEL-ICC showed well-differentiated glandular structures mimicking pseudolymphoma. Another case of EBV+IFDCS contained sparse inflammatory infiltrates and predominant spindle cell proliferation, resulting in potential misdiagnosis as a mesenchymal neoplasm. One IPT vs. IMT case demonstrated marked IgG4-positive plasma cell infiltration, raising the concern of IgG4-related disease. We also encountered a rare presentation of EBV+DLBCL with spindle cell morphology and focal follicular dendritic cell marker expression, closely simulating EBV+IFDCS. Our findings highlight critical morphologic and immunophenotypic distinctions among these diagnostically challenging lesions and provide practical strategies to avoid common pitfalls. These findings support a structured, morphology-driven diagnostic approach integrating EBER status, immunophenotype, and molecular testing to improve diagnostic precision in this challenging group of lesions.