Analysis of LGR5 Immunohistochemical Expression in Gastrointestinal Neuroendocrine Tumors
A C Iuga, Y Suarez, M Sabour, N Theise, N Harpaz, H Zhu. The Mount Sinai Medical Center, New York; Beth Israel Medical Center, New York
Background: LGR5, a recently de-orphanized G-protein couple receptor (GPCR) and Wnt pathway regulator, was shown to be expressed in murine intestinal stem cells. In human small intestine, LGR5 stains rare crypt base cells with neuroendocrine features. The expression of LGR5 in tumors with neuroendocrine differentiation has not been reported yet. We therefore aimed to study the expression of LGR5 in gastrointestinal neuroendocrine tumors.
Design: A tissue microarray of 44 gastrointestinal neuroendocrine tumors and 57 hepatic neuroendocrine tumor metastases were stained for LGR5 by immunohistochemistry (ab12827, Abcam; K5361, Dako). Thirty-four paired cases of primary tumors with their metastases were included. Normal pancreas and small intestine were used as control for staining. The LGR5 expression pattern was scored based on staining intensity and percentage of positive cells. The LGR5 staining was compared with the Ki67 index and the reported chromogranin and synaptophysin markers.
Results: In normal pancreas, LGR5 is strongly expressed in neuroendocrine (islet) cells. 88% of the primary (3/4 gastric, 23/24 intestinal, 13/14 pancreatic, 0/2 appendiceal) and 87% of the metastases stain positive for cytoplasmic LGR5. 67% of the tumors show similar LGR5 expression levels in their metastases. LGR5 is positive in the majority of the cases expressing chromogranin and synaptophysin (34/38). More interestingly, LGR5 was positive in the 7 cases negative for chromogranin and 5 negative for synaptophysin. In our study, twenty-three of the thirty seven cases with a Ki-67 index greater than 2% show weak or absent LGR5 expression. Only fourteen of the sixty two cases with a Ki67 index less than 2% have weak or absent LGR5. Thus, the partial or complete loss of expression correlates with an increased Ki67 index (>2%) (Fisher's exact test, p<0.05).
Conclusions: LGR5 is a novel immunohistochemical marker for gastrointestinal neuroendocrine tumors. LGR5 appears to also retain positivity in tumors that lost classical neuroendocrine marker expression. A possible explanation could be that LGR5 is a marker of early neuroendocrine differentiation that maintains its expression after other markers are lost. Interestingly, in our study, the loss of LGR5 expression correlates with an increased Ki67 index, therefore we suggest that it may be an indicator of poorer outcome.
Additional studies are needed to further confirm marker specificity. Given the widespread use of GPCR-targeting drugs in medicine, LGR5 may represent a novel target for neuroendocrine tumor chemotherapy.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 67, Wednesday Morning