Prognosis in adenocarcinomas of lower oesophagus, gastro-oesophageal junction and cardia evaluated by uPAR-immunohistochemistry Ole Didrik Lærum 1,2 , Kjell Ovrebo 3 , Arne Skarstein 3 , Ib Jarle Christensen 1 , Warner Alpı ´zar-Alpı ´zar 1,4 , Lars Helgeland 2 , Keld Danø 1 , Boye Schnack Nielsen 1,5 and Martin Illemann 1 1 The Finsen Laboratory, Copenhagen University Hospital, Copenhagen, Denmark 2 The Gade Institute, Section of Pathology, University of Bergen, and Department of Pathology, Haukeland University Hospital, Bergen, Norway 3 Department of Surgery, Haukeland University Hospital, and Department of Surgical Sciences, University of Bergen, Bergen, Norway 4 Cancer Research Program, Health Research Institute (INISA), and Center for Research on Microscopic Structures, University of Costa Rica, San Jose ´, Costa Rica 5 Bioneer A/S, Molecular Histology, Hørsholm, Denmark Adenocarcinomas of lower oesophagus, gastro-oesophageal junction and cardia in humans are highly invasive tumours with poor prognosis. The localisation of urokinase-type plasminogen activator receptor (uPAR) was determined in 66 patients; 60 with adenocarcinomas and six cases with Barrett’s oesophagus. uPAR was expressed in nearly all cases of invasive adenocarcinomas by populations of cancer cells, macrophages and myofibroblasts at both the invasion front and the tumour core. In areas with high-grade dysplasia or with Barrett’s metaplasia adjacent to the tumour tissue, no uPAR-immunoreactivity was found. High local expression of uPAR, therefore, appears to be a characteristic marker for invasive behaviour in this tumour, suggesting that uPAR’s contribution to matrix degradation during invasive growth is a late event in carcinogenesis. Using a scoring system for semiquantitative estimation of uPAR-positivity on immmunohistochemically stained specimens, a significant association was found between poor overall survival and high uPAR-score for cancer cells in the tumour core and for macrophages peripherally at the tumour invasion zone. In multivariate analysis, these two uPAR-scores were confirmed as highly significant prognostic parameters independent of Tumour, Node, Metastasis (TNM)-stage and World Health Organization (WHO) classification. The proteolytic action of these malignant and nonmalignant accessory cells thus seemed to follow two main patterns: one dominated by uPAR positive cancer cells and one by uPAR-positive macrophages. Scoring of uPAR- positivity might be a useful parameter for onset of invasion and prognosis in these adenocarcinomas. Adenocarcinomas of the lower oesophagus, the gastro-oeso- phageal junction and cardia represent an increasing health problem. On a worldwide basis, there are nearly half a mil- lion new cases every year, and due to an extremely bad prog- nosis, almost as many deaths. In addition, the diagnosis is usually made at a stage where the disease is already advanced. 1 In Europe and the USA, there has been an almost six-fold increase in the incidence of these tumours from 1975 to 2000. 2 These adenocarcinomas are now outnumbering the incidence of squamous carcinomas of oesophagus. 2 The latter tumours are mainly seen in men but the adenocarcinomas are also rapidly increasing among women. Key words: oesophagus, cardia, adenocarcinoma, Barrett’s metaplasia, uPAR, invasion Abbreviations: CI: confidence interval; E: tumour localisation in oesophagus; ECM: extracellular matrix; EG: tumour localisation in gastric- oesophageal junction; G: tumour localisation in cardia; HR: hazard ratio; mAb: monoclonal antibody; MMP: matrix metalloprotease; pAb: polyclonal antibodies; PAI: plasminogen activator inhibitor; PA-system: plasminogen activation-system; a-SMA: a-smooth-muscle-actin; SCC: squamous cell carcinoma; TNM: Tumour, Node, Metastasis; TNP: trinitrophenyl hapten; uPA: urokinase-type plasminogen activator; uPAR: uPA receptor; WHO: World Health Organization Additional Supporting Information may be found in the online version of this article. Grant sponsor: Danish Cancer Society, Dansk Kræftforsknings Fond, The Meyer Foundation, Else og Mogens Wedell-Wedellsborg Fond, Haukeland University Hospital (Helse-Vest), The European Commission; Grant number: LSHC-CT-2003-503297; European Community’s Seventh Framework Programme FP7/2007-2011 under grant agreement no 201279. DOI: 10.1002/ijc.26382 History: Received 29 Nov 2010; Accepted 21 Jul 2011; Online 22 Aug 2011 Correspondence to: Ole Didrik Lærum, The Gade Institute, Section of pathology, University of Bergen, Haukeland University Hospital, Bergen N-5021, Norway, Fax: þ86-20-87343535, E-mail: ole.laerum@gades.uib.no Cancer Cell Biology Int. J. Cancer: 131, 558–569 (2012) V C 2011 UICC International Journal of Cancer IJC