Molecular markers predicting lymph node metastasis in early esophageal cancer

Patrick S. Plum¹, Ute Warnecke-Eberz¹, Oulfa Dhaouadi¹, Hakan Alakus¹, Uta Drebber², Ralf Metzger¹, Klaus L. Prenzel¹, Arnulf H. Hölscher¹, Elfriede Bollschweiler<sup>1

1</sup>Department of General, Visceral and Cancer Surgery, University of Cologne and ²Institute of Pathology, University of Cologne, Cologne, Germany

Offprint requests to: Elfriede Bollschweiler, MD, Ph D, Department of General, Visceral and Cancer Surgery, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany. e-mail: Elfriede.Bollschweiler@uk-koeln.de

Summary. AIMS: The aim of this study was to identify molecular markers predicting depth of tumor infiltration and presence of lymph node metastasis in early esophageal cancer. METHODS: Between 1996 and 2004, 67 patients with pT1 esophagus cancer underwent esophagectomy. Resected tumors and lymph nodes were analyzed by immunohistochemistry for tissue infiltration, lymph node metastasis (LNM), micrometastasis and extracapsular lymph node infiltration (ELNI). We focused on MMP-2 (matrix-metalloproteinase-2), TIMP-2 (tissue inhibitor of metalloproteinase-2), PIM-1 and survivin as the most promising marker candidates. The data was correlated with the patients’ long term follow-up (median follow-up time 11.4 years). RESULTS: We found 22 pT1a and 45 pT1b carcinomas. None of the mucosal carcinomas, but 58% (26 patients) of the submucosal carcinomas showed lymph node metastasis or micrometastasis. The rate of LNM positively correlated with the depth of tumor infiltration (23% LNM in sm1 tumors and 82% LNM in sm3 tumors). Low grade PIM-1 expression (<30%) was significantly associated with occurrence of LNM (p=0.034) while high expression TIMP-2 (>70%) were detected in submucosal tumors. Logistic regression analysis revealed PIM-1 and Grading G3 as independent risk factors for LNM (p<0.001). Survival of patients with micrometastasis was comparable to those with LNM (median survival: 5.05 years versus 5.52 years). Patients with ELNI had the worst prognosis (median survival: 1.7 years). CONCLUSIONS: PIM-1 is a promising marker for prediction of lymph node metastasis in early esophagus cancer. Extracapsular lymph node infiltration has an independent worse prognostic impact. Histol Histopathol 30, 1193-1202 (2015)

Key words: Esophageal cancer, MMP-2, TIMP-2, PIM-1, Survivin, Lymph node metastasis, Extracapsular lymph node infiltration, Immunohistochemistry

DOI: 10.14670/HH-11-618