Podoplanin expression in peritumoral keratinocytes predicts aggressive behavior in extramammary Paget's disease

Publication date: Available online 27 March 2017
Source:Journal of Dermatological Science
Author(s): Zaigen Cho, Eiichi Konishi, Mai Kanemaru, Taro Isohisa, Takahiro Arita, Minako Kawai, Miho Tsutsumi, Hiromi Mizutani, Hideya Takenaka, Toshiyuki Ozawa, Daisuke Tsuruta, Norito Katoh, Jun Asai
BackgroundRecent studies have demonstrated podoplanin expression in several tumors, which has been associated with lymph node metastasis and poor prognosis. Podoplanin expression in peritumoral cells such as cancer-associated fibroblasts also correlates with tumor progression in several cancers. However, podoplanin expression and its association with extramammary Paget's disease (EMPD) remain unclear.ObjectiveIn this study, we examined whether the presence of podoplanin expression in tumor cells or peritumoral basal keratinocytes correlated with aggressive behavior in patients with EMPD and investigated the mechanisms of podoplanin-mediated tumor invasion in this disorder.MethodsSkin samples of 37 patients with EMPD were investigated by immunohistochemical analysis. The functions of podoplanin in keratinoctes were examined in vitro by RT-PCR and with invadopodia gelatin-degradation assays using HaCaT cells.ResultsPodoplanin was not identified in tumor cells in all cases. Podoplanin expression in peritumoral basal keratinocytes was observed in 25 patients (67.6%). In in situ EMPD, 50% of cases (9 in 18) exhibited podoplanin-positive keratinocytes, whereas 84.2% (16 in 19) demonstrated positive staining in invasive EMPD (P<0.05). Podoplanin expression in peritumoral keratinocytes was also associated with tumor thickness (P<0.005). By immunohistochemical analysis, podoplanin-positive peritumoral keratinocytes were found to be negative for E-cadherin, one of the major adhesion molecules of keratinocytes, which might contribute to tumor invasion into the dermis through a crack in the basal cell layer induced by down-regulation of cell adhesion therein. We further found that podoplanin-positive keratinocytes exhibited invadopodia, which are thought to function in the migration of cancer cells through tissue barriers, indicating that podoplanin-positive peritumoral basal keratinocytes might assist tumor invasion by degrading the extracellular matrix.ConclusionThe presence of podoplanin expression in peritumoral keratinocytes correlates with aggressive behavior in EMPD and might therefore serve as a useful prognostic marker for patients with EMPD.



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