Palladin is a Marker of Liver Metastasis in Primary Pancreatic Endocrine Carcinomas*


Background: Palladin is a metastasis-associated gene regulating cell motility. The expression of palladin protein in pancreatic neuroendocrine tumors (PET) and carcinomas (PECA) is not known. Materials and Methods: A tissue microarray (TMA) of well-differentiated (WD) PETs/PECAs (AJCC 2010) and non-neoplastic, histologically normal pancreatic tissue/islets (HNPIs) was immunostained with palladin antibody and quantified using the Allred score. The results were correlated with the presence or absence of liver metastases. Results: The retrospective study included 19 males and 19 females of age 27-79 years (mean 54). Tumor size was 0.9-11.5 cm (mean 3.8). Palladin expression was cytoplasmic and/or membranous. The tumors with high palladin expression were associated with liver metastasis (p<0.0001). All 14 primary PECA with hepatic metastases (MP-PECAs) exhibited palladin expression whereas 14 out of 24 (58%) clinicallylocalized primary PET (CLP-PETs) expressed palladin (p<0.01) with median Allred scores of 5 (range 3-7) and 2 (range 0-6) respectively (p<0.0001). The mean Allred score for the HNPIs in the MP-PECAs (N=6) was higher (4.2) as compared to that in the CLP-PETs (2.5,N=11) (p=0.23). Conclusion: Palladin may identify primary pancreatic endocrine neoplasms with a propensity to metastasize to the liver. Pancreatic neuroendocrine tumors/carcinomas (PETs/ PECAs) account for 1-2% of pancreatic neoplasms and are clinically challenging (1). The clinical behavior of PET is often unpredictable. According to the current American Joint Committee on Cancer (AJCC) Staging manual (2), well differentiated (WD) PECAs (WD-PECAs) are separated from well-differentiated PETs (WD-PETs) on the basis of gross invasion of the adjacent organs by the tumor (duodenum, stomach, spleen) and/or the presence of metastases. With the development of metastases, patient survival significantly drops and none of the currently available therapies offer cure. The discovery of molecular markers of metastases would offer newer objective criteria to determine patient prognosis and may improve our understanding of the biology of clinical progression in PET.
The metastasis-associated gene palladin has a role in cell motility and cell-cell interactions (4, 5). Palladin protein has been reported in a variety of tissues such as prostate, testis, ovary, small intestine, colon and smooth muscle (6). It is localized along the actin filaments of smooth muscle, epithelial and glial cells in a periodic punctuate pattern (4, 6). There are three isoforms of palladin (a 90 kDa, 140 kDa, and 200 kDa) of which the 90 kDa isoform is the most common and most abundant (5). Palladin is a critical well documented component of the cytoskeleton and co-localizes with alpha-actinin along with F-actin stress fibers (5). It belongs to a small gene family that includes the Z-disc proteins myopalladin and myotilin, all of which share similar Ig-like domains (7).

*This study was presented in part at the 6th Annual Meeting of the European Neuroendocrine Tumor Society (ENETS), Granada, Spain, March 5-7, 2009 and at the 98th Annual Meeting of the United States and Canadian Academy of Pathology, Boston, U.S.A., March 7-13, 2009.
*Both Authors contributed equally to this work.
Correspondence to: Domenico Coppola, Department of Anatomic Pathology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, U.S.A. Tel: +1 813 7453275,
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