High-grade lung adenocarcinoma with fetal lung-like morphology: Clinicopathologic, immunohistochemical, and molecular analyses of 17 cases

Shigeki Morita, Akihiko Yoshida, Akiteru Goto, Satoshi Ota, Koji Tsuta, Karin Yokozawa, Hisao Asamura, Jun Nakajima, Daiya Takai, Masaya Mori, Teruaki Oka, Junichi Tamaru, Shinji Itoyama, Koh Furuta, Masashi Fukayama, Hitoshi Tsuda

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52 Citations (Scopus)


Low-grade lung adenocarcinoma of fetal lung type, which is well characterized by its unique clinicopathologic and molecular features, is recognized as a distinct variant of lung cancer. In contrast, high-grade lung adenocarcinoma with fetal lung-like morphology (HG-LAFM) has not been studied widely. To characterize this subset better, we analyzed 17 highgrade adenocarcinomas with at least focal component resembling a developing epithelium in the pseudoglandular phase of the fetal lung. These rare (ca. 0.4%) carcinomas occurred predominantly in elderly men with a heavy smoking history, who showed elevated serum α-fetoprotein in 4 of 5 cases tested. Histologic examination revealed a fetal lung-like component as a focal finding accounting for 5% to 60% of the total tumor volume. It was invariably admixed with tissues having a morphology not resembling that of a fetal lung. A coexisting non-fetal lung-like element was quite heterogenous in appearance, showing various growth patterns. However, clear-cell (88%), hepatoid (29%), and large cell neuroendocrine carcinoma (24%) histology seemed overrepresented. HG-LAFM was characterized immunohistochemically by frequent expression of α-fetoprotein (41%), glypican-3 (88%), SALL-4 (59%), neuroendocrine markers (82%), CDX-2 (35%), and p53 (65%). HG-LAFM was molecularly heterogenous in that EGFR or KRAS mutation was observed in 22% of cases tested for both. Our data indicate that HG-LAFMs might form a coherent subgroup of lung adenocarcinomas. However, the uniformly focal nature of the fetal lung-like element, widely diverse coexisting non-fetal lung-like histology, and inhomogenous molecular profiles lead us to believe that HG-LAFM is best regarded as a morphologic pattern showing characteristic association with several clinicopathologic parameters rather than a specific tumor entity.

Original languageEnglish
Pages (from-to)924-932
Number of pages9
JournalAmerican Journal of Surgical Pathology
Issue number6
Publication statusPublished - 2013 Jun
Externally publishedYes


  • Adenocarcinoma
  • Fetal
  • Lung
  • Neuroendocrine

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine


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