Journal of Pathology J Pathol 2010; 220: 551–561 Published online 11 December 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/path.2673 Original Paper Up-regulation of L1CAM is linked to loss of hormone receptors and E-cadherin in aggressive subtypes of endometrial carcinomas Monica Huszar, 1# Marco Pfeifer, 2# Uwe Schirmer, 2 Helena Kiefel, 2 Gottfried E Konecny, 3 Alon Ben-Arie, 4 Lutz Edler, 5 Maria M¨ unch, 5 Elisabeth M¨ uller-Holzner, 6 Susanne Jerabek-Klestil, 6 Samira Abdel-Azim, 6 Christian Marth, 6 Alain G Zeimet, 6 Peter Altevogt 2 * and Mina Fogel 1 1 Department of Pathology, Kaplan Medical Centre, Rehovot, Israel 2 Tumour Immunology Programme, D015, German Cancer Research Centre, D-69120 Heidelberg, Germany 3 David Geffen School of Medicine, University of California, Los Angeles, CA, USA 4 Department of Gynecology, Kaplan Medical Centre, Rehovot, Israel 5 Biostatistics Group R0700, German Cancer Research Centre, D-69120 Heidelberg, Germany 6 Department of Gynecology and Obstetrics, Medical University of Innsbruck, 6020 Innsbruck, Austria *Correspondence to: Peter Altevogt, Tumour Immunology Programme, D015, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. E-mail: P.Altevogt@dkfz.de # These authors contributed equally to this study. Conflict of interest: Mina Fogel and Peter Altevogt hold patents for the application of LI antibodies in human tumour therapy. Received: 7 September 2009 Revised: 18 November 2009 Accepted: 6 December 2009 Abstract Endometrial carcinomas (ECs) are classified into type 1 (less aggressive) and type 2 (aggressive) tumours that differ in genetic alterations. So far, reliable immunohistochemical markers that can identify patients with high risk for recurrence are rare. We have defined the expression of L1 cell adhesion molecule (L1CAM), a biomarker previously identified for EC, and compared its expression to oestrogen receptor (ER)/progesterone receptor (PR) and E-cadherin. We found that L1CAM was absent in normal endometrium and the vast majority of endometrioid ECs (type 1) but was strongly expressed in serous and clear-cell ECs, considered as type 2. 78/272 cases were identified as L1CAM-positive endometrioid ECs that were correlated with a poor prognosis. Strikingly, we observed an inverse relationship between L1CAM and ER/PR/E-cadherin expression in all ECs. In mixed ECs, composed of endometrioid (L1CAM - ER/PR + E-cadherin + ) and clear-cell/serous (L1CAM + ER/PR - E-cadherin - ), both phenotypes were co-expressed. In some of these cases L1CAM was up- regulated at the leading edge of the tumour, where ER/PR and E-cadherin expression were selectively lost. In EC cell lines treated with the epithelial–mesenchymal transition (EMT) inducer TGFβ 1, L1CAM and vimentin were strongly up-regulated, while E-cadherin expression was reduced. The treatment also resulted in an increased expression of the EMT transcription factor Slug and an enhanced cell invasion. Depletion of Slug by siRNA knockdown prevented both L1CAM up-regulation and enhanced cell invasion. According to our analysis, we suggest that L1CAM is a novel marker for EMT in ECs and that L1CAM- typing could identify endometrioid ECs that have type 2-like features and are at high risk for recurrence. Copyright  2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Keywords: immunohistochemistry; ER/PR; E-cadherin; L1; EMT Introduction Endometrial carcinomas (ECs) are subdivided into two pathogenic categories: type 1, consisting of most endometrioid and mucinous ECs; and type 2, rep- resented largely by serous and clear-cell ECs [1]. The type 1 tumour is preceded by oestrogen-induced hyperplasias, tends to be low grade and low stage, and is associated with hormone-related risk factors and a good prognosis [1,2]. Type 2 carcinomas are usually found in atrophic endometrium, unrelated to oestrogenic abnormalities, often diagnosed with disseminated disease, and have a poor prognosis [3,4]. Types 1 and 2 ECs can be distinguished at the molec- ular level. Immunohistochemical data indicate that the pattern of ER/PR, p53 and Her-2/neu expression in type 2 differs from that of type 1 carcinomas [4–6]. Type 1 ECs are associated with PTEN inactivation and express ER/PR [7], whereas in type 2 ECs the ER/PR expression is usually lost and p53 mutations are present. Despite this definite classification, women with early-stage endometrioid ECs, which by conven- tional measures have a good prognosis, develop recur- rence and eventually die of the disease. Because of the Copyright  2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk