Prognostic impact of cancer-associated stromal cells in patients with stage I lung adenocarcinoma.
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.
Department of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba; Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba; Division of Respiratory Medicine, Department of Medicine, Shiga University of Medical, Science, Otsu, Shiga, Japan.
Masami
M
Ito
Department of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba. Electronic address: gishii@east.ncc.go.jp.
Genichiro
G
Ishii
Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba.
Kanji
K
Nagai
Department of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba; Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba.
Ryo
R
Maeda
Division of Respiratory Medicine, Department of Medicine, Shiga University of Medical, Science, Otsu, Shiga, Japan.
Yasutaka
Y
Nakano
Department of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba.
Atsushi
A
Ochiai
D000230:Adenocarcinoma / Q000175:diagnosis* / Q000473:pathology* / Q000601:surgery; D000368:Aged; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000473:pathology* / Q000601:surgery; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology* / Q000401:mortality; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D000098853:Podoplanin
D008562:Membrane Glycoproteins; D051117:Scavenger Receptors, Class A; C495139:MSR1 protein, human; C117468:PDPN protein, human; D000098853:Podoplanin