Differences between low and high grade fetal adenocarcinoma of the lung: a clinicopathological and molecular study

Abstract

Background: Fetal adenocarcinoma of the lung (FLAC) is a rare entity of lung cancer. It is classified into low-grade fetal adenocarcinoma (L-FLAC) and high-grade fetal adenocarcinoma (H-FLAC). We aim to report the clinicopathological and molecular features of FLAC in Chinese patients.

Methods: FLACs were screened from a consecutive lung adenocarcinoma series comprising 920 cases. The clinicopathological features L-FLAC and H-FLAC were retrospectively reviewed via immunohistochemical study and mutation analysis.

Results: Three L-FLAC and five H-FLAC cases were identified. L-FLAC mainly occurred in young patients and was predominantly in stage I upon diagnosis and conferred favorable outcomes. L-FLAC tumors were characterized by the glycogen-rich columnar cells lining the complex glandular structures, with low nuclear atypia, morule formation, and mainly nuclear- and cytoplasmic-localized β-catenin expression. In contrast, H-FLAC predominantly occurred in elderly men with a history of smoking. The stage of H-FLAC was often advanced at presentation and had a poor prognosis. H-FLAC tumors exhibited more prominent atypia of the nucleus, the absence of morule formation, and largely membrane-localized β-catenin. All 5 H-FLACs were immunohistochemically characterized by overexpression of the p53 protein; the L-FLAC tumors were negative for p53. Two cases of H-FLAC were positive for AFP. No Her-2 or ALK-D5F3 overexpression was observed in any of the tumors. EGFR L858R point mutation was identified in one of the H-FLAC cases. EGFR T790M mutation was detected in one of the L-FLAC cases. No mutations in KRAS, PIK3CA or BRAF were detected.

Conclusions: L-FLAC and H-FLAC exhibited distinctive clinicopathological, immunophenotypic and molecular features with potential prognostic value.

Keywords: Fetal adenocarcinoma; clinicopathology; immunohistochemistry; lung; mutation.

Conflict of interest statement

Conflicts of Interests: The authors have no conflicts of interest to declare.

Figures

Figure 1

Histology and immunophenotype of an L-FLAC case. This tumor consists of complex glandular structures lined with glycogen-rich columnar cells, with low nuclear atypia, and morule formation (A, H&E ×200).Immunohistochemically, the tumor cells express aberrant nuclear and cytoplasmic β-catenin (B, ×200). Meanwhile, they are positive for TTF-1 (C, ×200) and negative for p53 (D, ×200).

Figure 2

H-FLAC exhibits the absence of morules, broad areas of necrosis, and complex acinar glands that consist of columnar tumor cells with supranuclear or subnuclear cytoplasmic clearing, large vesicular nuclei, prominent nucleoli (A: H&E, ×100; B: H&E, ×200). Immunohistochemically, the tumor cells show membranous staining of β-catenin (C, ×200). Meanwhile, they are negative for TTF1 (D, ×200); the cells are positive for p53 (E, ×200) and AFP (F, ×200).