Pancreatic Neuroendocrine Cancer

Pancreatic neuroendocrine tumor (PNET) refers to several tumor types located in the pancreas. These tumors are classified as functional or nonfunctional depending on production and secretion of bioactive hormones. Functional PNETs cause clinical symptoms associated with their tumor classification. Some examples include gastrinomas, which are associated with gastrointestinal ulcers and diarrhea; glucagonomas, which are associated with diabetes, skin rash, and diarrhea; and vasoactive intestinal polypeptide tumors, which may produce extreme watery diarrhea, abdominal pain, and flushing. Because nonfunctional PNETs do not produce bioactive hormones and do not cause clinical symptoms, these tumor types (eg, pancreatic polypeptidoma) are diagnosed at a more advanced stage, often presenting with symptoms related to mass effect or metastasis (eg, abdominal pain, obstructive jaundice, or weight loss). PNET is relatively rare, with an incidence of <1 in 100,000. Most diagnoses occur in patients aged >40 years, with equal gender distribution. Causation of PNET is sporadic but associated less commonly with genetic syndromes (eg, multiple endocrine neoplasia type 1 or von Hippel-Lindau).

The malignant potential for PNET is determined by clinical symptoms and presence of metastatic disease rather than a specific immunohistochemistry profile. In addition, neuroendocrine tumors (NETs) are classified according to their degree of pathologic differentiation. Well-differentiated NETs typically include low and intermediate grades, whereas poorly differentiated NETs are considered biologically aggressive. Historically, staging of PNETs used the classification system of the World Health Organization, in which PNETs were considered (1) well-differentiated of benign or uncertain behavior, (2) welldifferentiated with low malignant potential, or (3) poorly differentiated with high-grade malignant potential based on the proliferation index of the Ki67 marker. The European Neuroendocrine Tumor Society (ENETS) developed a system of grading that uses both the Ki67 proliferation index and the number of mitoses per high-power field. More recently, ENETS and the American Joint Committee on Cancer each proposed a TNM staging system.

Treatment of PNET

Treatment of PNET is dependent on functional status as well as the absence or presence of metastatic disease. Optimal therapy for PNET includes medications (eg, somatostatin analogs, proton pump inhibitors) to control clinical symptoms followed by surgical resection, such as pancreaticoduodenectomy (also known as the Whipple procedure) or distal pancreatectomy, of the primary tumor. Surgical resection of hepatic metastases from PNET has a low morbidity and mortality rate and is recognized as the recommended treatment modality if >90% of a patient’s tumor burden is resectable.

Metastatic disease is not always amenable to surgical resection and requires alternative treatments, such as regional hepatic therapy (eg, radiofrequency ablation, arterial embolization, chemoembolization, and radioembolization) or peptide receptor radio - nucleotide therapy, which is currently only used outside the United States. These treatments are not curative but may be used for symptom palliation or disease control. Orthotopic liver transplantation has been attempted in a small subset of patients, but it has not received empirical support.