Pathology

Pancreatic endocrine tumors are commonly termed neuroendocrine tumors. However, some researchers indicate that it is unclear whether these tumors originate from the pancreatic islets.3 Pancreatic endocrine tumors may contain ductu-lar structures; may produce hormones that are not produced by the normal pancreas, including gastrin and vasoactive intestinal polypeptide (VIP); and may produce more than one hormone.3"5 These findings suggest that pancreatic endocrine tumors originate from dedifferentiation of an immature pancreatic stem cell.4 The finding of ductular structures in these tumors has led to the suggestion that these tumors are ductular in origin.6 Further, these tumors may appear to be papillary and cystic in structure.7

It has also been proposed that pancreatic endocrine tumors originate from cells that are part of the diffuse neuroendocrine system: amine precursor uptake and decarboxylation tumors (APUDomas).8"10 These tumor cells contain dense secretory granules, may produce multiple peptides, and usually stain positive for neuron-specific enolase, chromogranin A, and synaptophysin.3,5,11 APUDomas comprise many neuroendocrine tumors, including carcinoids, medullary thyroid carcinoma, and pheochromocytomas.8"10 Microscopically, pancreatic endocrine tumors are composed of sheets of small, round cells with uniform nuclei and cytoplasm (Fig. 84-1). Mitotic figures are rare, and the precise determination of malignancy cannot be made on the basis of histologic appearance.6,12

Studies suggest that there is an aggressive and a nonaggressive form of pancreatic neuroendocrine tumor. The aggressive form comprises glucagonoma, somatostatinoma, and most nonfunctional tumors. It is more common in patients without multiple endocrine neoplasia type 1 (MEN 1). It is characterized by a short disease duration, large pancreatic tumors, liver metastases, and a long-term survival rate as low as 20% to 50%. This may also apply to liver metastases. Some liver neuroendocrine tumors demonstrate slow growth and progression, whereas others grow rapidly. Those with rapid growth are associated with decreased survival.

Studies have shown a number of clinical and tumoral factors that are predictors of aggressive growth (Table 84-1). These include liver metastases, lymph node metastases, local invasion, large primary tumor size, nonfunctional tumor, and incomplete tumor resection. The further definition of other factors is likely to have a significant impact on the surgical management of pancreatic neuroendocrine tumors; that is, aggressive tumors will require more aggressive surgery.

TABLE 84 -2 Syndromes Associated with Rare Pancreatic Endocrine Tumors

FIGURE 84-1. Duodenal somatostatinoma. Sheets of uniform-appearing, small, round cells with rare mitotic activity are present within this tumor, which occurs in the submucosal layer of the duodenum. This tumor stained positively for somatostatin by immunocytochemistry. It was detected by palpation of the duodenum at the time of cholecystectomy.

FIGURE 84-1. Duodenal somatostatinoma. Sheets of uniform-appearing, small, round cells with rare mitotic activity are present within this tumor, which occurs in the submucosal layer of the duodenum. This tumor stained positively for somatostatin by immunocytochemistry. It was detected by palpation of the duodenum at the time of cholecystectomy.

The molecular pathogenesis of pancreatic neuroendocrine tumors is just being elucidated and holds promise for the identification of important parameters. Studies have demonstrated that alterations in the tumor suppressor gene DPC4 located on 18q21 are involved in tumorigenesis.13 Unfortunately, at present, no gene alteration sufficiently predicts aggressive behavior to allow a different, more aggressive treatment strategy to be implemented.

Determination of malignancy is best made by either radiographic or surgical pathologic documentation of metastases to either regional lymph nodes or the liver.

TABLE 84-1. Characteristics of Aggressive Pancreatic Neuroendocrine Tumors

Liver metastases Liver metastases progression Lymph node metastases Extranodal/extrahepatic metastases Local invasion Primary tumor size >3 cm Nonfunctional tumor Poor tumor differentiation Incomplete tumor resection

Tumor Syndrome

TABLE 84 -2 Syndromes Associated with Rare Pancreatic Endocrine Tumors

Tumor Syndrome

Somatostatinoma

Steatorrhea

Diabetes

Gallstones

Glucagonoma

Rash

Diabetes

Cachexia

Thrombophlebitis

VIPoma

Diarrhea

GRFoma

Acromegaly

Corticotropin-producing tumoi

Cushing's syndrome

Tumor releasing PTHrP

Hypercalcemia

Neuiotensinoma

Diarrhea

Hypotension

Flushing

PPoma or nonfunctional

None

VIP - vasoactive intestinal polypeptide; GRF = growth hormone-releasing factor; PTHrP = parathyroid hormone-related protein; PP = pancreatic polypeptide,

VIP - vasoactive intestinal polypeptide; GRF = growth hormone-releasing factor; PTHrP = parathyroid hormone-related protein; PP = pancreatic polypeptide,

Pancreatic endocrine tumors are classified according to the functional syndrome they produce (Table 84-2). Every type of pancreatic endocrine tumor may be associated with MEN 1, and it is important to recognize this association because these patients generally have multiple tumors and a more indolent natural history.14 Several studies suggest that, in addition to MEN 1, pancreatic neuroendocrine tumors are found in higher frequency in patients with von Recklinghausen's disease,1517 von Hippel-Lindau disease,18 and tuberous sclerosis.19 In patients with von Recklinghausen's disease, duodenal somatostatinoma and gastrinoma have been reported.1517 Of patients with von Hippel-Lindau disease, 17% had pancreatic endocrine tumors, including both adenomas and carcinomas. However, it is unusual for these tumors to be functional, and few patients have a clinical hormonal syndrome. Patients with tuberous sclerosis may have a higher incidence of insulinoma and nonfunctional pancreatic neuroendocrine tumors.

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