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The history of classication and staging of pNETs is complex and has undergone a great number of changes in the last 10–15years. Currently, the WHO, European Neuroendocrine Tumor Society (ENETS), and American Joint Committee on Cancer (AJCC) have each proposed a formal staging system for pNETs [25–27]. The 2010 WHO classication system is based on the proliferative activity of the tumor as measured by mitotic count and the expression of nuclear antigen Ki-67, a marker for cellular proliferation. Grade 1 tumors have fewer than 2 mitoses per 10 high power elds and less than or equal to 3% Ki-67 staining. Grade 2 tumors have 2–10 mitoses per 10 high power elds or 3–20% Ki-67 staining. Grade 3 tumors have greater than 20 mitoses per 10 high power elds or greater than 20% Ki-67 staining. Grade 1 and 2 lesions are well differentiated and classied as NETs (90% of tumors), while Grade 3 lesions are poorly differentiated and classied as neuro­endocrine carcinomas (10% of tumors). The WHO classication system is summa­rized in Table9.1 [26]. The ENETS staging system is based on TNM classication (Table9.2), while the AJCC staging system is taken from the TNM staging system developed for pancreatic adenocarcinoma (Table9.3) [26, 27]. Most head-to-head comparisons of the ENETS and the AJCC staging systems have shown no statistical difference in their ability to predict survival [28, 29]; however, one cohort study did nd a slight advantage favoring the ENETS system [30]. In the face of three

pNETs are divided into functional versus nonfunctional tumors with about 90% being classied as nonfunctional. Commonly, tumors are dened as nonfunctional if the patient does not suffer from symptoms due to hormone hypersecretion, even

ghrelin, human choriogonadotropin (hCG), and renin) that are not normally expressed in the islets are expressed by PNETs. The expressed hormones may or may not be secreted or biologically active, and the hormone expression prole of each tumor can change over time. It is common that an initially nonfunctioning PNET later triggers hormonal hypersecretion syndrome [37–39].

contains multiple endocrine tumors. These tumors, however, virtually never pro­duce detectable amounts of gastrin. Sporadic gastrinomas, occurring either in the pancreas or in the duodenum, are apparently solitary tumors. In the pancreas, they usually have a diameter of 2cm or more, whereas in the duodenum their diameter is most often less than 1cm [79]. Metastasis to regional lymph nodes is found in approximately 60% of patients with pancreatic gastrinomas [80] and at an even higher percentage in patients with duodenal gastrinomas. Because duodenal gastri­nomas can metastasize while still very small, they may give rise to periduodenal lymph node metastases which are larger than the primary. It has therefore been sug­gested that so-called peripancreatic and periduodenal lymph node gastrinomas may be metastases of duodenal microgastrinomas that were overlooked during surgery, rather than true primary tumors [81, 82]. In contrast to the distribution of lymph node metastases, duodenal gastrinomas, whether sporadic or associated with MEN1, seem to give rise to liver metastases in a smaller percentage of cases than pancreatic gastrinomas. Thus 10-year survival rates have been shown to be higher in patients with duodenal gastrinomas (84%) than in patients with pancreatic gastrinomas (57%) [83]. Histologically, gastrinomas most often show a trabecular or pseudo­glandular pattern. Immunocytochemically, gastrin can be demonstrated in almost all tumors. Approximately 50% of gastrinomas are multihormonal and contain PP, glu­cagons, and/or insulin in addition to gastrin. Islet hyperplasia and nesidioblastosis have repeatedly been described in the non-neoplastic pancreas of patients with gas­trinomas, but these ndings could not be conrmed by morphometry [84]. Recently, however, morphometrically dened PP-cell hyperplasia has been described in the ventrally derived region of the pancreatic head [85]. So far it has not been denitely established what inuence hypergastrinemia may have on these changes. In the gas­tric mucosa, however, sustained hypergastrinemia induces parietal cell hyperplasia with thickened mucosal folds and gastric acid hypersecretion. In addition, the num­ber of enterochromafn-like (ECL) cells is increased in the fundic mucosa [86, 87]. ECL cell tumors in the fundus of the stomach, which are a well-known complication in patients suffering from pernicious anemia with chronic type A gastritis, appear to be very uncommon in patients with sporadic ZES. They have, however, been reported in patients with ZES and MEN1. In these instances, they probably repre­sent another neoplastic manifestation of the MEN1 syndrome rather than merely the result of a trophic effect of gastrin [

attached to the pancreas, and are most often malignant. Tumors containing glucagon­producing cells that are not associated with the glucagonoma syndrome are often benign and are usually found as small neoplasms at autopsy or in a MEN1 pancreas [89, 90]. Immunocytochemically, glucagonomas often stain weakly for glucagon, but also show reactivity for peptides derived from proglucagon (glicentin, glucagon­like peptides 1 and 2) [91]. In addition, numerous PP cells can often be identied. Electron microscopically, readily identiable A-cell granules may be recognized in functionally silent glucagon-producing tumors, whereas atypical secretory granules predominate in glucagonomas associated with the syndrome.