Prognostic Implications of Cytoplasmic and Nuclear Overexpression of Lipocalin-2/NGAL in Colorectal Adenocarcinoma (CRC)

9 11 2009

KA Robstad, JD Choate, CE Sheehan, JS Ross and DM Jones
Department of Pathology, Albany Medical College, Albany, NY

Lipo 20x

Lipocalin-2 Stain at 20x

Background:  The lipocalin family is a diverse group of secreted soluble proteins that bind hydrophobic ligands and act as small molecule transporters.  Lipocalin-2, also known as neutrophil gelatinase-associated lipocalin (NGAL), is an inflammatory cytokine upregulated in acute inflammatory conditions which has been found to be over-expressed in various human malignancies including carcinomas of the breast, ovary, pancreas and colon.  The prognostic significance of Lipocalin-2 expression in CRC has not been previously investigated.

Design: Formalin-fixed, paraffin-embedded sections from 156 colorectal adenocarcinomas (CRCs) were immunostained by an automated method (Ventana Medical Systems; Tucson, AZ) using rat monoclonal lipocalin-2/NGAL (R&D Systems, Minneapolis, MN).  Cytoplasmic and nuclear immunoreactivity was semi quantitatively evaluated based on both intensity (weak, moderate and intense) and distribution (focal <10%, regional 10 to 50% and diffuse >50%) and results were correlated with clinicopathologic variables.

Result: Lipocalin-2 immunoreactivity was predominately cytoplasmic, however, significant nuclear immunoreactivity was noted in a subset of cases.  Intense diffuse cytoplasmic overexpression of lipocalin-2 was observed in 30/156 (19%) of CRC and correlated with early AJCC stage (28% of stage I/II vs 11% of stage III/IV; p=0.007) and presence of concomitant Crohn’s disease (100% with Crohn’s vs 0% without Crohn’s).  Nuclear lipocalin-2 immunoreactivity was noted in 6 cases, all 6 of which (100%) were lymph node negative (p=0.005), early stage (p=0.015), and moderately differentiated/grade 2 (p=0.102) tumors.  Lipocalin-2 over-expression did not correlate with disease recurrence or overall survival. On multivariate analysis, pathologic stage at diagnosis independently predicted patient survival.

Conclusion: Cytoplasmic lipocalin-2 over-expression is associated with both early AJCC tumor stage as well as the presence of pre-existing Crohn’s disease potentially reflecting its role as an inflammatory cytokine.  Nuclear expression, only identified in a small subset of CR, was found to correlate significantly with low-stage, moderately differentiated, lymph node-negative tumors. Further studies of both nuclear and cytoplasmic lipocalin-2 expression in CRC appear warranted.

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