title: High-grade fetal adenocarcinoma of the lung is a tumour with a fetal phenotype that shows diverse differentiation, including high-grade neuroendocrine carcinoma: a clinicopathological, immunohistochemical and mutational study of 20 cases.
abstract: OBJECTIVE
  High-grade fetal adenocarcinoma (H-FLAC) is a rare variant of pulmonary adenocarcinoma; this study aims to elucidate its clinicopathological features and genetic abnormalities.
  
  
  RESULTS
  Clinicopathological, immunohistochemical and mutational analyses were performed on 20 surgically resected lung cancers that showed H-FLAC histology in various proportions. These tumours predominantly occurred in elderly males and in 10 patients who were heavy smokers. Four cases were pure H-FLAC, and 16 cases were mixed H-FLAC, which were found to be combined with conventional-type adenocarcinoma (15 cases), large-cell neuroendocrine carcinoma (three cases), small-cell carcinoma (one case), enteric adenocarcinoma (two cases), choriocarcinoma (two cases), and a solid-clear cell pattern (seven cases). The fetal phenotype and diverse differentiation were supported by the immunoexpression of α-fetoprotein (95%), thyroid transcription factor-1 (TTF-1) (50%), neuroendocrine markers (30-45%), proneural markers (50-69%), and CDX2 (40%). Except for TTF-1 expression (pure H-FLACs, 0%; mixed H-FLACs, 63%), there were no significant differences in histological or immunohistochemical findings between pure and mixed H-FLACs. EGFR, KRAS, BRAF and PIK3CA mutations were identified in 20%, 0%, 0% and 7% of the tumours, respectively.
  
  
  CONCLUSIONS
  Lung adenocarcinomas with H-FLAC features possess the potential for multidirectional differentiation, and are not strongly associated with known major driver gene mutations.
authors: Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan.|Department of Pathology, Chiba University Hospital, Chiba, Japan.
authors: Masaki
authors: M
authors: Suzuki
authors: Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Takuya
authors: T
authors: Yazawa
authors: Department of Pathology, Chiba University Hospital, Chiba, Japan.
authors: Satoshi
authors: S
authors: Ota
authors: Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Junichi
authors: J
authors: Morimoto
authors: Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Ichiro
authors: I
authors: Yoshino
authors: Department of Pathology, Yokohama City University Hospital, Yokohama, Japan.
authors: Shoji
authors: S
authors: Yamanaka
authors: Department of Pathology, Yokohama City University Medical Centre, Yokohama, Japan.
authors: Yoshiaki
authors: Y
authors: Inayama
authors: Department of Pathology, Saitama Cardiovascular and Respiratory Centre, Kumagaya, Saitama, Japan.
authors: Yoshinori
authors: Y
authors: Kawabata
authors: Department of Pathology, Saitama Cardiovascular and Respiratory Centre, Kumagaya, Saitama, Japan.
authors: Yoshihiko
authors: Y
authors: Shimizu
authors: Department of Pathology, Yamamoto Kumiai General Hospital, Noshiro, Japan.
authors: Masayo
authors: M
authors: Komatsu
authors: Department of Pathology, Kurashiki General Hospital, Kurashiki, Japan.
authors: Kenji
authors: K
authors: Notohara
authors: Department of Pathology, Fujieda Municipal General Hospital, Fujieda, Japan.
authors: Kenji
authors: K
authors: Koda
authors: Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan.|Department of Pathology, Chiba University Hospital, Chiba, Japan.
authors: Yukio
authors: Y
authors: Nakatani
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D000509:alpha-Fetoproteins
keywords: fetal adenocarcinoma; genetic analysis; neuroendocrine carcinoma; α-fetoprotein; β-catenin