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Distinct properties of pure- and mixed-type high-grade fetal lung adenocarcinomas by genetic profiling and transcription factor expression

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Abstract

The clinicopathological differences among high-grade fetal lung adenocarcinomas completely comprising tumor cells that resemble fetal lung epithelium (pure type) and those with fetal lung-like components admixed with conventional adenocarcinoma cells (mixed type) remain undetermined. Here, we examined the clinicopathological, immunohistochemical, and molecular features of 11 lung adenocarcinomas with fetal lung-like morphology among 3895 consecutive cases of primary lung cancer based on the expression pattern of transcription factors. According to the current WHO classification, two cases (0.05%) were categorized as low-grade fetal adenocarcinoma, two cases (0.05%) were pure-type high-grade fetal adenocarcinoma, five cases (0.1%) were mixed-type high-grade fetal adenocarcinoma, and the remaining two cases (0.05%) were lung adenocarcinoma with high-grade fetal features (fetal lung-like morphology occupied less than 50%). CTNNB1 mutations were exclusively identified in low-grade fetal adenocarcinomas. In contrast, mixed-type high-grade fetal adenocarcinoma or lung adenocarcinoma with high-grade fetal features frequently harbored mitogenic drivers including EGFR mutations. Furthermore, almost all tumor cells expressed CDX2 and HNF4α in both cases of pure-type high-grade fetal lung adenocarcinoma, but lacked TTF-1 positivity. In contrast, TTF-1 was frequently expressed in mixed-type high-grade fetal lung adenocarcinoma and in lung adenocarcinoma with high-grade fetal features. Our data suggest similar prevalence of low-grade fetal lung adenocarcinoma and pure-type high-grade fetal lung adenocarcinoma, and indicate that pure- and mixed-type high-grade fetal lung adenocarcinomas are distinct, with the former akin to low-grade fetal adenocarcinoma with respect to purely embryonic morphology and absence of common lung adenocarcinoma mitogenic drivers, and the latter being genetically and transcriptionally related to conventional lung adenocarcinoma.

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Acknowledgements

This work was performed in part at the Intractable Disease Research Center, Juntendo University.

Funding

This work was supported in part by a Grant-in-Aid from the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number 19K07469) and Practical Research for Innovative Cancer Control (grant number JP18ck0106252) from the Japan Agency for Medical Research and Development (AMED). This work was also supported in part by the Takeda Science Foundation.

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Authors and Affiliations

  1. Department of Human Pathology, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Satsuki Kishikawa, Takuo Hayashi, Tsuyoshi Saito, Keita Sasa, Noriko Sasahara & Takashi Yao

  2. Department of General Thoracic Surgery, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan

    Kazuya Takamochi & Kenji Suzuki

  3. Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan

    Keita Sasa & Yoshiyuki Suehara

  4. Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan

    Fumiyuki Takahashi

  5. Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan

    Shinji Kohsaka

Authors
  1. Satsuki Kishikawa
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  2. Takuo Hayashi
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  4. Kazuya Takamochi
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  7. Fumiyuki Takahashi
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  10. Kenji Suzuki
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Contributions

Satsuki Kishikawa, Takuo Hayashi, Tsuyoshi Saito, Noriko Sasahara, and Takashi Yao provided histopathological and immunohistochemical information. Kazuya Takamochi and Kenji Suzuki provided patients’ clinical information. Satsuki Kishikawa, Takuo Hayashi, Tsuyoshi Saito, Kazuya Takamochi, Keita Sasa, Yoshiyuki Suehara, Fumiyuki Takahashi, and Shinji Kohsaka conceived molecular experiments and analyzed data. All authors were involved in writing the paper and had final approval of the submitted and published versions. Takuo Hayashi takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

Corresponding author

Correspondence to Takuo Hayashi.

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Ethics approval

The information contained in, and preparation of, this manuscript comply with the journal’s ethical standards. The study design was approved by the Institutional Review Board of Juntendo University (no. 2020264).

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The authors declare no competing interests.

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Supplementary information

Supplemental Fig. 1.

Hematoxylin-eosin staining of lung adenocarcinomas resembling the fetal lung (PDF 4752 kb). All cases exhibited at least one focal area resembling fetal lung epithelium.

Supplemental Fig. 2.

Representative immunohistochemical findings for SMARCA4 and SMARCB1. Tumor cell showed nuclear expression of SMARCA4 (case 4) and SMARCB1 (case 3) expression. (PDF 8924 kb)

Supplemental Fig. 3.

EGFR and CTNNB1 mutations in a case of mixed-type high-grade fetal lung adenocarcinoma. A. Genomic DNA was extracted from non-fetal and fetal lung-like components. EGFR and CTNNB1 mutations were detected in both components. B. Tumor cells in non-fetal and fetal lung-like components showed focal nuclear staining in lung adenocarcinoma with mixed fetal lung-like elements harboring CTNNB1 mutations. Note that tumor cells exhibited strong membranous expression of E-cadherin in both non-fetal and fetal lung-like components. (PDF 17933 kb)

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Kishikawa, S., Hayashi, T., Saito, T. et al. Distinct properties of pure- and mixed-type high-grade fetal lung adenocarcinomas by genetic profiling and transcription factor expression. Virchows Arch 480, 609–619 (2022). https://doi.org/10.1007/s00428-021-03247-7

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  • DOI: https://doi.org/10.1007/s00428-021-03247-7

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