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. 2010 Oct;134(10):1520-7.
doi: 10.5858/2009-0114-OA.1.

Podoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survival

Haruhisa Kitano  1 , Shun-Ichiro Kageyama, Stephen M Hewitt, Ryuji Hayashi, Yoshinori Doki, Yoshitomo Ozaki, Shozo Fujino, Mikiko Takikita, Hajime Kubo, Junya Fukuoka
Affiliations

Podoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survival

Haruhisa Kitano et al. Arch Pathol Lab Med. 2010 Oct.

Abstract

Context: Podoplanin is a mucin-type glycoprotein and a lymphatic endothelial marker. Immunohistochemical staining for podoplanin is currently used as a routine pathologic diagnosis tool in Japan to identify lymphatic invasion of cancer cells. Recent reports suggest that podoplanin and other proangiogenic molecules are expressed in stromal fibroblasts and myofibroblasts.

Objective: To analyze the distribution of podoplanin expression in tumor stroma and its clinical and biologic significance.

Design: We performed immunohistochemistry for podoplanin on tissue microarrays from 1350 cases of 14 common cancer types.

Results: Two hundred eighty-seven of 662 cases (43%) showed podoplanin expression in the stromal cells within cancer nests. Stromal podoplanin expression in 14 common cancer types was significantly associated with tumor stage (P < .001), lymph node metastases (P < .001), lymphatic invasion (P = .02), and venous invasion (P < .001). The stromal cells positive for podoplanin were also positive for α-smooth muscle actin but negative for desmin, confirming a myofibroblasts phenotype. In contrast, myofibroblasts in inflammatory fibrotic lung diseases were podoplanin negative. Lymphatic vessel density was greater in the stromas with podoplanin expression than in the stroma lacking podoplanin-expressing stromal cells (P = .01). Survival data were available for non-small cell lung cancer. Stromal podoplanin expression was associated with poorer prognosis in adenocarcinoma (P < .001) and remains statistically significant after adjustment for sex, age, and stage (P = .01).

Conclusion: Our data indicate that podoplanin expression in stromal myofibroblasts may function as a proangiogenic biomarker and may serve as a predictive marker of lymphatic/vascular spread of cancer cells and a prognostic marker of patient survival.

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Figures

Figure 1.
Figure 1.
Immunohistochemical detection of podoplanin in cancerous stroma. A, Validation of podoplanin immunohistochemical staining using podoplanin transfected NIH3T3 cells. Paraffin-embedded cells demonstrate membranous signals in 10% to 20% of cells (original magnification ×400). B and C, Images of a tissue microarray. B, Overview of multiple cancer tissue microarray with podoplanin staining. Each group has either 100 or 50 cores from 1 cancer type. A total of 1150 cases from 14 different cancer types are included (scale bar = 1 cm). C, Representative core positive for anti-podoplanin staining in cancerous stromal cells (diameter of the core is 0.6 mm). D through F, High-power view of cancerous stroma stained with hematoxylin-eosin (D), anti-podoplanin (E), and anti-α-smooth muscle actin (F) using consecutive sections (original magnifications ×400 [D through F]). Arrowheads indicate nonneoplastic spindle cells seen in the cancerous stroma. Identical cells are positive for podoplanin and α-smooth muscle actin. Spindle cells positive for podoplanin were considered as myofibroblasts based on the staining patterns and morphology (asterisk in E, lymphatic vessel stained with podoplanin). G, Cancerous stromal cells and lymphatic vessels (arrowheads) are positive for podoplanin (original magnification ×100). Lymphatic vessels stained more intensely with podoplanin than did stromal spindle cells.
Figure 2.
Figure 2.
The mean numbers of lymphatic vessels in the stroma with podoplanin (Pod) positive (+) and negative (−) expression. The numbers were counted in the area of a ×20 (1.3 mm2) objective. Lymphatic vessel densities in the podoplanin-positive stroma were higher than those in podoplanin-negative stroma (P = .01, t tests).
Figure 3.
Figure 3.
Survival analysis of podoplanin expression in cancerous stromal cells in lung cancer patients. Kaplan-Meier (KM) curves comparing survival between cases with podoplanin negative (−) in cancerous stroma and those with podoplanin positive (+). A, KM curve in non-small cell lung cancer cases. B, KM curve in adenocarcinoma cases. C, KM curve in squamous cell carcinoma cases.
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