Intense Expression of EGFR L858R Characterizes the Micropapillary Component and L858R Is Associated with the Risk of Recurrence in pN0M0 Lung Adenocarcinoma with the Micropapillary Component

  • Naoto Kishi
  • Masaoki Ito
  • Yoshihiro Miyata
  • Akinori Kanai
  • Yoshinori Handa
  • Yasuhiro Tsutani
  • Kei Kushitani
  • Yukio Takeshima
  • Morihito OkadaEmail author
Translational Research and Biomarkers



Lung adenocarcinoma with the micropapillary (MP) component poses a higher risk of recurrence even when the MP component is not predominant. This study explored genetic features associated with highly malignant behavior of lung adenocarcinoma with the MP component.


The MP and papillary (PaP) components were captured separately in three patients. Comprehensive mRNA expressions of somatic variants were compared between the MP and PaP components of each patient using next-generation sequencing (NGS). The protein expression of the NGS-detected variant was validated by immunohistochemistry. The prognostic impact of the detected variant was evaluated in 288 adenocarcinoma patients with resection of pN0M0.


In two cases, NGS suggested higher RNA expression of EGFR L858R in the MP component than in the PaP component (allele frequency, 0.485 vs. 0.155 and 1.000 vs. 0.526, respectively; P < 0.001 for both). Immunohistochemistry validated intense expression of L858R in the MP component of 27 MP-positive (MP+) patients. Among 288 pN0M0 patients, L858R was more frequently harbored in the MP+ patients than in the MP-negative (MP−) patients. The MP+ patients harboring L858R showed significantly worse recurrence-free survival (RFS) than the MP+ patients without L858R (median RFS 38.7 and 55.0 months, respectively; hazard ratio [HR] 3.004; 95% confidence interval [CI] 1.306–9.132; P = 0.012). Multivariate analysis of the MP+ patients showed that positive L858R status was associated with poorer RFS (HR 2.976; 95% CI 1.190–7.442; P = 0.020).


EGFR L858R was more frequently harbored in the MP+ adenocarcinoma patients than in the MP− adenocarcinoma patients. Intense expression of L858R in the MP component was suggested, and the MP+ patients harboring L858R were at comparatively higher risk of recurrence in the group with pN0M0 lung adenocarcinoma.



This study was conducted in part at the Analysis Center of Life Science, Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan. The authors thank Editage ( for English language editing.


There are no conflicts of interest.

Supplementary material

10434_2019_7854_MOESM1_ESM.xlsx (15 kb)
Supplementary material 1 (XLSX 14 kb)


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Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  • Naoto Kishi
    • 1
  • Masaoki Ito
    • 1
  • Yoshihiro Miyata
    • 1
  • Akinori Kanai
    • 2
  • Yoshinori Handa
    • 1
  • Yasuhiro Tsutani
    • 1
  • Kei Kushitani
    • 3
  • Yukio Takeshima
    • 3
  • Morihito Okada
    • 1
    Email author
  1. 1.Department of Surgical Oncology, Research Institute for Radiation Biology and MedicineHiroshima UniversityHiroshimaJapan
  2. 2.Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and MedicineHiroshima UniversityHiroshimaJapan
  3. 3.Department of Pathology, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan

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