title: Podoplanin expression in peritumoral keratinocytes predicts aggressive behavior in extramammary Paget's disease.
abstract: BACKGROUND
  Recent 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.
  
  
  OBJECTIVE
  In 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.
  
  
  METHODS
  Skin samples of 37 patients with EMPD were investigated by immunohistochemical analysis. The functions of podoplanin in keratinocytes were examined in vitro by RT-PCR and with invadopodia gelatin-degradation assays using HaCaT cells.
  
  
  RESULTS
  Podoplanin 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Zaigen
authors.initials: Z
authors.lastname: Cho
authors.affiliation: Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Konishi
authors.affiliation: Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Kanemaru
authors.affiliation: Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Isohisa
authors.affiliation: Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Arita
authors.affiliation: Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Kawai
authors.affiliation: Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Tsutsumi
authors.affiliation: Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Mizutani
authors.affiliation: Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hideya
authors.initials: H
authors.lastname: Takenaka
authors.affiliation: Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuruta
authors.affiliation: Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Norito
authors.initials: N
authors.lastname: Katoh
authors.affiliation: Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan. Electronic address: jasai@koto.kpu-m.ac.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Asai
mesh_terms: D000368:Aged; D015820:Cadherins / Q000032:analysis; D002465:Cell Movement; D002478:Cells, Cultured; D005260:Female; D005833:Genital Neoplasms, Female / Q000473:pathology*; D005834:Genital Neoplasms, Male / Q000473:pathology*; D006801:Humans; D015603:Keratinocytes / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000502:physiology*; D009361:Neoplasm Invasiveness; D010145:Paget Disease, Extramammary / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D000098853:Podoplanin
chemical_list: D015820:Cadherins; D008562:Membrane Glycoproteins; D016212:Transforming Growth Factor beta; C117468:PDPN protein, human; D000098853:Podoplanin
keywords: Extramammary Paget's disease; Invasion; Keratinocyte; Metastasis; Podoplanin