Because of the difficulty in determining which PETs are malignant, many pathologists use the term carcinoma for all PETs, or malignant. The WHO 2010 neuroendocrine neoplasm classification has introduced PLX4032 concentration grading and staging; low to intermediate grade tumors are defined as neuroendocrine tumors (previously carcinoids) whereas high-grade carcinomas are termed neuroendocrine carcinomas (20). Pathologists are becoming Inhibitors,research,lifescience,medical to accept the WHO (2010) grading system, adopted from the European Neuroendocrine Tumor Society (ENTS)

proposal for grading all gastoenteropancreatic neuroendocrine tumors (21). In addition Inhibitors,research,lifescience,medical to the 3-tier grade-based classification, TNM staging of PETs can now be performed (AJCC/UICC) using the same parameters applied for exocrine type carcinomas of the pancreas (22). The newly updated WHO 2010 classification scheme uses a proliferation-based grading system together with the classical histopathological diagnostic criteria for PETs (Table 2) (19). In the WHO 2010 classification, the malignant potential Inhibitors,research,lifescience,medical of pancreatic neuroendocrine neoplasms is acknowledged and enforced. The fact is that PETs

are often malignant because they are metastatic at diagnosis, or at least have the potential to metastasize Inhibitors,research,lifescience,medical in a size-dependent fashion. The new classification aims to standardize

current diagnostic and management procedures and enable systematic and prognostically Inhibitors,research,lifescience,medical relevant patient stratification. PETs are graded into 1 of 3 tiers, either as well-differentiated neuroendocrine tumors or poorly-differentiated neuroendocrine carcinomas, on the basis of stage-pertinent features such as proven invasion or metastasis (5). Table 2 WHO 2010 classification and grading of PETs (5,21) The grading system still remains controversial, but clear signs of malignancy include metastasis and local or extrapancreatic Linifanib (ABT-869) invasion. Other characteristics that appear helpful in determining prognosis are tumor size and functional status, necrosis, mitotic activity, perineural invasion and angioinvasion, and possibly CD44 isoform upregulated expression and cytokeratin 19 immunostaining (5,23). Peptide production detected in the serum or by immunohistochemistry is not a prognostic factor for nonfunctional PETs (3). Nuclear pleomorphism is also not a useful predictor; however some studies have demonstrated a correlation between overall nuclear grade and prognosis (24).