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BACKGROUND AND HISTORICAL ELEMENTS

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Oberdorfer first described a tumor different from classic adenocarcinoma in the early 1900s, and referred to it as “karzinoid.” Historically, carcinoid has been the term to describe neuroendocrine tumors of the gastrointestinal (GI) tract. In reality, neuroendocrine tumors (NETs) are a heterogeneous group of tumors, including tumors originating from the stomach, pancreas, small bowel, rectum, appendix, and lung among other organs, and as a result there is a wide range of clinical courses. Because neuroendocrine cells secrete a variety of hormones and regulatory proteins, these tumors can secrete functional hormones. Carcinoid syndrome describes flushing, diarrhea, and cardiac valvular dysfunction associated with serotonin production, but tumors can produce a variety of hormones including gastrin, insulin, somatostatin, and glucagon. The GI tract and the pancreas are the most common site for NET formation, and they often metastasize to the liver through the portal vein. Because the primary tumors often have an indolent course, metastatic disease to the liver can be the primary presentation. This chapter focuses on the diagnosis and management of gastroenteropancreatic (GEP) neuroendocrine metastases to the liver.

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EPIDEMIOLOGY

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Gastrointestinal and pancreatic NETs are the second most common malignancy of the digestive system.1 The incidence has increased markedly over the last 40 years.2 The incidence of all NETs including GEP tumors increased in the United States from an incidence ratio (IR) of 1 between 1973 and 1977 to IR of 3.65 between 2003 and 2007. In a population-based Canadian study, from 1994 to 2009, the incidence increased from 2.48 per 100,000 to 5.86 per 100,000, equivalent to a 2.36-fold increase.3 This has been shown to be secondary to increased detection.3 An estimated 70% to 80% of NETs are nonfunctional and peak incidence is 70 to 79 years old.4 Approximately 8.3% to 77% of patients with pancreatic NETs (pNETs)and 67% to 91% of patients with small intestine (or midgut) NETs develop liver metastases.5

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RISK FACTORS

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There are few identified risk factors associated with GEP neuroendocrine malignancies. pNETs can be associated with Von-Hippel-Lindau (VHL) syndrome, multiple endocrine neoplasia 1 (MEN1), neurofibromatosis, and tuberous sclerosis. Upwards of 80% of patients with MEN1 have pNET and 10% to 20% of patients with neurofibromatosis and VHL syndrome. It is rare in tuberous sclerosis. Primary tumors of the pancreas and small bowel are most likely to develop liver metastases.

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MOLECULAR BIOLOGY

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Pancreatic NETs have been studied extensively for molecular genetic alterations. The majority of pNETs occur sporadically; however, they also may be a part of MEN1, VHL syndrome, or neurofibromatosis. MEN1 demonstrates a defect on chromosome 11q13; MENIN, a 610 amino acid protein; VHL syndrome, a defect on chromosome 17q11.2; VHL, a 213 amino acid protein; and a gene on chromosome 17q11.2 neurofibromin, a 2485 amino acid protein. Malignant insulinomas demonstrate a high loss of heterozygosity (LOH) for markers on chromosome 22q (93%).6

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Activating mutations in the ras family ...

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