Hepatoid adenocarcinoma of the lung: clinicopathologic and molecular analysis of 17 cases

Hepatoid adenocarcinoma of the lung (HAL) is a rare subtype of non-small cell lung carcinoma characterized by morphologic and immunophenotypic overlap with hepatocellular carcinoma (HCC), creating diagnostic challenges for practicing pathologists. Because of its rarity, only limited information exists regarding its molecular profile and biologic behavior. We retrospectively analyzed 17 HAL cases diagnosed at Northwestern Memorial Hospital and describe their clinical presentation, morphologic features, immunohistochemical and molecular profiles, and clinical outcomes. Histologically, HAL is composed of polygonal to columnar epithelioid cells with abundant lightly eosinophilic, finely granular cytoplasm and predominantly solid and/or complex glandular growth patterns. Foci of mucinous differentiation may be present. Cytologic atypia, brisk mitotic activity, and tumor necrosis are common findings. Immunohistochemically, HAL is characterized by strong and diffuse HepPar1 expression, positivity for adenocarcinoma markers such as MOC31, and cytoplasmic immunoreactivity for TTF-1. Across the 17 cases, STK11 alterations were most frequent (52.9%), followed by TP53 (41.2%) and KRAS (35.3%). Concurrent KRAS + STK11 alterations were identified in 23.5% of cases, compared with The Cancer Genome Atlas (TCGA) cohorts of other lung adenocarcinomas (11/566, 2.0%) and HCC (0/372, 0%). HAL demonstrates highly aggressive behavior, with metastatic presentation even in low-stage tumors (T1: 33.3%; T2: 71.4%), frequent hematogenous spread, and death of disease in 41.2% of patients at a median follow-up of 5 months. In summary, HAL is a distinct subtype with characteristic morphologic and immunohistochemical features. Given its aggressive clinical course, accurate diagnosis is essential for patient management.