Dynamic nature of hepatic differentiation in lung adenocarcinoma

Hepatic differentiation in lung adenocarcinomas, including hepatoid adenocarcinomas, is rare. We encountered a case of lung adenocarcinoma with distinct cytoplasmic TTF-1 expression, which is characteristic of neoplastic and non-neoplastic hepatocytes, and confirmed positivity for hepatic markers, including hepatocyte paraffin 1 (HepPar1) and glypican-3. This prompted a retrospective analysis of hepatic differentiation in lung adenocarcinoma.

Among 123 surgically resected lung tumours, 1 adenocarcinoma (0.1%) showed positivity for HepPar1, hepatocyte nuclear factor 4-alpha and cytoplasmic TTF-1, with heterogeneous expression confined to part of the tumour. This heterogeneity led us to investigate expressional variations in hepatic differentiation during the clinical course. In an analysis of 992 patients with at least two specimens collected during treatment, hepatic differentiation, identified via HepPar1 expression, was present in at least one specimen in 8 patients, with cytoplasmic TTF-1 expression used as a reference. Notably, in 7 of 8 patients, hepatic differentiation emerged or expanded with disease progression, suggesting its dynamic nature and potential association with disease progression.

The observed variability in hepatic marker expression over the clinical course suggests that hepatic differentiation may be a dynamic process influenced by treatment or disease progression, rather than a static characteristic of a distinct tumour entity. In routine practice, hepatic differentiation is tracked using cytoplasmic TTF-1 expression.