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Original Research: Lung Cancer |

Tumor Budding Correlates With the Protumor Immune Microenvironment and Is an Independent Prognostic Factor for Recurrence of Stage I Lung AdenocarcinomaTumor Budding in Lung Adenocarcinoma

Kyuichi Kadota, MD, PhD; Yi-Chen Yeh, MD; Jonathan Villena-Vargas, MD; Leonid Cherkassky, MD; Esther N. Drill, MS; Camelia S. Sima, MD; David R. Jones, MD, FCCP; William D. Travis, MD, FCCP; Prasad S. Adusumilli, MD, FCCP
Author and Funding Information

From the Thoracic Service, Department of Surgery (Drs Kadota, Yeh, Villena-Vargas, Cherkassky, Jones, and Adusumilli), Department of Pathology (Drs Kadota and Travis), Department of Epidemiology & Biostatistics (Ms Drill and Dr Sima), and Center for Cell Engineering (Dr Adusumilli), Memorial Sloan Kettering Cancer Center, New York, NY; and Department of Diagnostic Pathology, Faculty of Medicine (Dr Kadota), Kagawa University, Kagawa, Japan.

CORRESPONDENCE TO: Prasad S. Adusumilli, MD, FCCP, Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065; e-mail: adusumip@mskcc.org


Preliminary data from this study were presented at the World Conference on Lung Cancer, October 27-31, 2013, Sydney, NSW, Australia.

FUNDING/SUPPORT: This work was supported by grants from the National Institutes of Health [R21 CA164568-01A1, R21 CA164585-01A1, R01 CA136705-06, U54 CA137788, P50 CA086438-13, and P30 CA008748], the US Department of Defense [PR101053 and LC110202], Mr William H. Goodwin and Mrs Alice Goodwin, the Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center.

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


Chest. 2015;148(3):711-721. doi:10.1378/chest.14-3005
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BACKGROUND:  Immune cell infiltration associated with tumor capsule disruption and tumor budding has been shown to reflect invasiveness, metastasis, and unfavorable prognosis in colorectal cancer. We investigated the influence of tumor budding on prognosis and its association with the immune microenvironment in lung adenocarcinoma.

METHODS:  Tumor slides from resected stage I lung adenocarcinomas were reviewed (n = 524 and n = 514, for training and validation cohorts, respectively) for assessment of tumor budding. CD3+ and forkhead box P3+ (FoxP3+) lymphocytes, CD68+ macrophages, IL-7 receptor, and IL-12 receptor β2 were analyzed using tissue microarrays constructed from tumor and stroma. Probability of recurrence was calculated using the competing risks method.

RESULTS:  In the training cohort, risk of recurrence for high-grade tumor budding was higher than it was for low-grade tumor budding (32% vs 12%, P < .001), which was confirmed in the validation cohort (P = .005). Tumor budding stratified the risk of recurrence for acinar-predominant (22% vs 9%, P < .001), papillary-predominant (22% vs 13%, P = .045), and solid-predominant (39% vs 19%, P = .022) tumors. Tumor budding was associated with higher stromal FoxP3+ lymphocyte infiltration, higher stromal FoxP3/CD3 risk index, higher tumoral and stromal CD68+ macrophage infiltration, and IL-7 receptor overexpression (P < .001, all associations). Tumor budding remained independently associated with recurrence on multivariate analysis (hazard ratio, 1.61; P = .008).

CONCLUSIONS:  Tumor budding is an independent prognostic factor of stage I lung adenocarcinoma and correlates with the protumor immune microenvironment. Our findings advocate investigating tumor-immune cell interactions at the invading edge as a biologic driver of tumor aggressiveness.

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