Flat Cell Variant of Lung Adenocarcinoma In Situ

Adenocarcinoma in situ (AIS) of the lungs has been increasingly diagnosed worldwide following the establishment of its diagnostic criteria along with advances in computed tomography imaging technology. We encountered a series of AISs with a peculiar flat cell morphology that were challenging to diagnose using the current diagnostic criteria. Histologically, all 5 tumors showed a lepidic pattern consisting of flat tumor cells with minimal nuclear atypia. Intra-alveolar mucin was identified in 4 cases, although cytoplasmic mucin of the tumor cells was inconspicuous. All tumors harbored genetic or immunohistochemical features of neoplasms identical to those of conventional AIS. Driver mutations were detected in 3 tumors (2 EGFR mutations and 1 ERBB2 mutation), and 4 tumors were positive for hepatocyte nuclear factor 4 alpha, although the intensity was very low. We also identified a flat cell variant of minimally invasive adenocarcinoma, suggesting a stepwise progression similar to that in conventional AIS. These findings suggest that AIS with flat cellular features is a morphologic variant of AIS and may be challenging to diagnose if pathologists are unaware of this atypical feature of lung neoplasm.