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Original Research |

Prognostic Impact of Cancer-Associated Stromal Cells in Patients With Stage I Lung AdenocarcinomaStromal Cells Are Important Recurrence Predictors

Masami Ito, MD; Genichiro Ishii, MD; Kanji Nagai, MD; Ryo Maeda, MD; Yasutaka Nakano, MD; Atsushi Ochiai, MD; International Association for the Study of Lung Cancer International Staging Committee
Author and Funding Information

From the Department of Pathology, Research Center for Innovative Oncology (Drs Ito, Ishii, Maeda, and Ochiai), and Department of Thoracic Oncology (Drs Ito, Nagai, and Maeda), National Cancer Center Hospital East, Kashiwa, Chiba; and Division of Respiratory Medicine (Drs Ito and Nakano), Department of Medicine, Shiga University of Medical, Science, Otsu, Shiga, Japan.

Correspondence to: Genichiro Ishii, MD, PhD, Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, 277-8577, Japan; e-mail address: gishii@east.ncc.go.jp

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

Funding/Support: This work was supported by the Grant-in-Aid for Cancer Research [19-10] from the Ministry of Health, Labour, and Welfare, the Foundation for the Promotion of Cancer Research, 3rd-Term Comprehensive 10-Year Strategy for Cancer Control, Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, and Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (JSPS KAKENHI) [20590417, 215981].


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

Funding/Support: This work was supported by the Grant-in-Aid for Cancer Research [19-10] from the Ministry of Health, Labour, and Welfare, the Foundation for the Promotion of Cancer Research, 3rd-Term Comprehensive 10-Year Strategy for Cancer Control, Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, and Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (JSPS KAKENHI) [20590417, 215981].


Chest. 2012;142(1):151-158. doi:10.1378/chest.11-2458
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Background:  The tumor microenvironment, of which cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) are the major cellular components, plays an important role in tumor progression. This study evaluated the significance of podoplanin-positive CAFs and CD204-positive TAMs, which may reflect tumor-promoting CAFs and TAMs, as risk factors for recurrence in patients with stage I lung adenocarcinoma.

Methods:  The expression of podoplanin in CAFs and CD204 in TAMs was analyzed by immunohistochemistry in 304 patients with stage I lung adenocarcinoma who underwent surgical resection between September 1992 and July 2004. The recurrence-free proportion (RFP) was estimated using the Kaplan-Meier method.

Results:  The presence of podoplanin-positive CAFs and the higher number of CD204-positive TAMs were associated with a lower 5-year RFP (P < .001 and P = .001, respectively). Podoplanin-positive CAFs were an independently statistically significant risk factor for recurrence with the highest hazard ratio (3.474, P = .029, by multivariate Cox proportional hazards model). According to subgroup analyses combining podoplanin-positive CAFs and other independent risk factors (visceral pleural invasion and intratumoral vascular invasion), the 5-year RFPs were 95.6%, 92.3%, 80.5%, and 30.3% (P = .294, P = .067, and P < .001) for patients with zero, one, two, or three risk factors, respectively.

Conclusions:  Podoplanin-positive CAFs were the most powerful independent risk factor for recurrence in patients with stage I lung adenocarcinoma. Podoplanin-positive CAFs may be useful for identifying patients with a high risk of recurrence who might benefit from adjuvant chemotherapy.

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