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

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

SUBMITTER: Zhang J

PROVIDER: S-EPMC5542993 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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Project description:BackgroundFetal adenocarcinoma of the lung is a rare variant of lung adenocarcinoma and is subcategorized into low-grade and high-grade (H-FLAC) fetal adenocarcinoma. We previously reported poor prognosis in pulmonary adenocarcinomas with an H-FLAC component; however, the genetic abnormalities involved in H-FLAC remain unclear. Therefore, this study aimed to elucidate molecular abnormalities as potential therapeutic targets for H-FLACs.MethodsWe performed immunohistochemical analysis and comprehensive genetic analyses using whole-exome sequencing in 16 lung cancer samples with an H-FLAC component. DNA was extracted from formalin-fixed paraffin-embedded tissues after macrodissection of the H-FLAC component.ResultsCancer-related mutations were identified in TP53 (7/16 cases), KMT2C (6/16 cases), KRAS (4/16 cases), NF1 (3/16 cases), STK11 (3/16 cases), CTNNB1 (2/16 cases), and EGFR (1/16 cases). A high tumor mutation burden of ≥10 mutations per megabase was observed in 3/16 cases. A high microsatellite instability was not detected in any case. Based on the cosine similarity with the Catalogue of Somatic Mutations in Cancer mutational signatures, H-FLACs were hierarchically clustered into three types: common adenocarcinoma-like (five cases), surfactant-deficient (ten cases), and signatures 2 and 13-related (one case). All common adenocarcinoma-like cases presented thyroid transcription factor-1 (TTF-1) expression, whereas surfactant-deficient cases often presented loss of TTF-1 and surfactant protein expression and included cases with mutations in the surfactant system genes NKX2-1 and SFTPC. H-FLACs displayed low programmed death ligand-1 (PD-L1) expression (1-49% of tumor cells) in 5/16 cases, and no case displayed high PD-L1 expression (≥50% of tumor cells).ConclusionsThis study indicates that lung cancers with an H-FLAC component rarely harbor currently targetable driver gene mutations for lung cancer but display a high frequency of KMT2C mutations. The microsatellite instability, tumor mutation burden, and PD-L1 expression status suggest a poor response to immune checkpoint therapy.

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

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