Research Papers:

Pathologic heterogeneity of lung adenocarcinomas: A novel pathologic index predicts survival

Geewon Lee _, E-Ryung Choi, Ho Yun Lee, Ji Yun Jeong, Joong Hyun Ahn, Seonwoo Kim, Jungmin Bae, Hong Kwan Kim, Yong Soo Choi, Jhingook Kim, Jaeil Zo, Kyung Soo Lee and Young Mog Shim

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Oncotarget. 2016; 7:70353-70363. https://doi.org/10.18632/oncotarget.11857

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Geewon Lee1,2,*, E-Ryung Choi1,*, Ho Yun Lee1, Ji Yun Jeong3, Joong Hyun Ahn4, Seonwoo Kim4, Jungmin Bae1, Hong Kwan Kim5, Yong Soo Choi5, Jhingook Kim5, Jaeil Zo5, Kyung Soo Lee1, Young Mog Shim5

1Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

2Department of Radiology and Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea

3Department of Pathology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea

4Biostatistics Team, Samsung Biomedical Research Institute, Seoul, Korea

5Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

*These authors have contributed equally to this work

Correspondence to:

Ho Yun Lee, email: [email protected]

Ji Yun Jeong, email: [email protected]

Keywords: lung adenocarcinoma, heterogeneity, pathology, subtype, survival

Received: April 29, 2016    Accepted: August 24, 2016    Published: September 06, 2016


Although the most predominant subtype of invasive lung adenocarcinoma has been reported to have clinical significance, a major limitation of this concept is that most tumors are mixed-subtype. Therefore, we aimed to determine the individual prognostic significance of each subtype and also attempted to establish a pathologic index that reflects the pathologic subtypes and overall heterogeneity of lung adenocarcinomas and evaluated its prognostic significance. The individual prognostic impact of each subtype was assessed from the development cohort using the disease-free survival (DFS) curve of a previous large-scale study. Hazard ratios (HRs) from the development cohort were 1, 1.025, 1.059, 1.495, and 1.160 for the lepidic, acinar, papillary, micropapillary, and solid pattern subtype, respectively. Based on the calculated HR of each subtype, four indices representing pathologic heterogeneity were developed. The first and second indices were defined as the sum of the proportions of each subtype multiplied by their HRs, with the addition of either entropy or Gini coefficient, respectively. The third index was calculated as the sum of all subtype percentages multiplied by their HRs. To emphasize heterogeneity, the fourth index was defined as the simple arithmetic sum of the scores of the subtypes multiplied by their HRs. Each subtype was assigned a score of 0 if the subtype was absent and a score of 1 if the subtype was present in a binary fashion. We applied these four pathologic indices to a validation group of 148 patients with comprehensive histologic subtyping for completely resected lung adenocarcinomas. DFS curves were plotted and predictive ability of each pathologic index was evaluated. Among the four pathologic indices, only pathologic index 3 enabled significant patient stratification in the validation cohort according to DFS (P = 0.004) and showed the highest Harrell’s C index of 0.691 of all four pathologic indices. In conclusion, we estimated the HR of each subtype and generated four pathologic indices that reflect heterogeneity. One of these, index 3, the pathologic heterogeneity index based on the sum of all subtype percentages multiplied by their HR, possesses good prognostic ability for predicting survival in patients with lung adenocarcinoma.

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