A distinctive form of lung adenocarcinoma that closely mimics large-cell neuroendocrine carcinoma is described. The tumors arose in 6 women and 6 men aged 46–86 years (mean=58.4). They presented as peripheral subpleural masses measuring 2–12 cm (mean=6.5 cm). Histologically they were characterized by islands or anastomosing and serpiginous strands of large, atypical cells showing striking peripheral palisading of nuclei, with high mitotic activity and prominent comedo-like areas of necrosis. Because of the striking resemblance to neuroendocrine tumors, some of the cases were initially diagnosed as large-cell neuroendocrine carcinoma despite the absence of neuroendocrine markers. Immunohistochemistry showed positivity of the tumor cells for TTF1 and napsin-A, and negative staining for p40. The tumors were also uniformly negative for multiple neuroendocrine markers, including chromogranin, synaptophysin, CD56, and INSM1. Electron microscopy performed in 2 cases was negative for membrane-bound dense core neurosecretory granules. Pathogenic alterations were detected in 5 of 8 tumors tested by next-generation sequencing. Point mutations in KRAS and TP53 were identified in 5 patients. Low-level amplification of GNAS, KIT, and FGFR1 was present in 2 patients. No RB1 mutations were identified. Clinical follow-up in 10 cases showed that 2 patients died of their tumors, 2 experienced distant metastases, and 6 were alive and well from 1 to 13 years after diagnosis (median=7.1 y). Large-cell basaloid adenocarcinoma is an unusual variant of lung cancer that is easily confused with large-cell neuroendocrine carcinoma. Awareness of this unusual variant of lung adenocarcinoma is important for treatment and prognosis and for avoiding misdiagnosis.
