Is Islet 1 (Isl1) a Sensitive and Specific Marker for Pancreatic Neuroendocrine Tumors and Their Metastases
Rondell P Graham, Bijayee Shrestha, Bolette L Caron, Thomas C Smyrk, Karen L Grogg, Ricardo V Lloyd, Lizhi Zhang. Mayo Clinic, Rochester, MN; University of Wisconsin, Madison, WI
Background: Islet 1 (Isl1) is a transcription factor involved in the development of pancreatic islet cells. An Isl1 antibody has been shown to be a sensitive lineage marker of pancreatic neuroendocrine tumors (NETs) and their metastases. However, the specificity of this marker has not been studied in a large series of NETs and their metastases from specific anatomic sites.
Design: A total of 244 primary NETs and 40 NETs metastatic to the liver from known primaries were studied. The primary sites were confirmed by pathology and radiology reports and clinical history. The primary tumors included: pancreas (N=102), stomach (N=10), duodenum (N=9), ileum (N=16), appendix (N=22), lung (N=17), colorectal (N=15), breast (N=12) and ovary (N=1). The hepatic metastases were from the pancreas (N=21), jejunum (N=2), ileum (N=12), cecum (N=1), rectum (N=2), and lung (N=2). Immunostaining was performed using antibodies to Isl1 (clone 1H9, 1:800, Abcam, MA) and CDX2 (AMT28; 1:50, Novocastra, UK), and nuclear staining in at least 5% of the tumor cells was considered positive. The correlation of Isl1 and CDX2 expression was studied using a tissue microarray (TMA) containing 46 pancreatic NETs. Combined staining of Isl1 and CDX2 was performed in a subset of NETs from other sites.
Results: Isl1 was positive in 90% of pancreatic, 89% of duodenal, 67% of colorectal, 14% of appendiceal, and 6% of ileal primaries. Isl1 was negative in all lung, gastric, breast and ovarian NETs. In addition, 76% of pancreatic (16 of 21) and 2 of 2 colorectal NETs metastatic to the liver were positive for Isl1 while all metastases from jejunal, ileal, cecal and lung primaries were negative. Thus, the overall sensitivity of Isl1 in identifying primary pancreatic NETs was 88% with a specificity of 80%. 78% pancreatic NETs in the TMA were positive for Isl1; 9% of these, all of which were negative for Isl1, were positive for CDX2. CDX2 was positive in only a few duodenal (2/9) or colorectal NETs (2/15).
Conclusions: This study confirms that Isl1 is a sensitive marker to support pancreatic origin in the case of metastatic NET. However, this study highlights that Isl1 does not allow for clear distinction from duodenal and colorectal NETs, even in combination with CDX2. Clinical/radiological correlation is required to exclude these primaries. Pathologists should be cautious in the use of Isl1 immunohistochemistry without a panel of other markers for determining the primary site of metastatic NETs.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 253, Wednesday Morning