Reviews in Basic and Clinical GastroenterologyGastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors
Section snippets
Epidemiology
PETs occur in 0.5%–1.5% of autopsies but are functional or symptomatic in less than 1 in 1000, resulting in a clinical detection rate of 1:100,000 population, which comprises 1%–2% of pancreatic neoplasms.8 In older studies, nonfunctional PETs (NF-PETs), insulinomas, and gastrinomas had equal frequency;9 however, in recent studies NF-PETs were twice as frequent.10, 11 The relative frequency of PETs varies in surgical or medical series, but most studies suggest a relative order of: NF-PET >
Classification/Pathology
PETs are divided clinically into 2 groups: functional and NF-PETs. Functional PETs secrete biologically active peptides causing 1 of 9 well-established syndromes (Table 1). NF-PETs are not associated with a specific hormonal syndrome either because no peptide is secreted or the substance secreted does not cause specific symptoms. Most (>70%) NF-PETs are not truly nonfunctional because they secrete substances such as pancreatic polypeptide, other peptides (neurotensin, ghrelin, and so forth),
Molecular Pathogenesis
Little is known about the molecular pathogenesis of PETs.1, 2, 8 This has occurred in part because alterations in common oncogenes (fos, jun, myc, k-ras, and so forth) or common tumor-suppressor genes (p53, retinoblastoma, and so forth) are not generally implicated in their pathogenesis.1, 2, 8 Some of the most important insights have come from studies of inherited PET syndromes.1, 2, 8, 20 Altered genes causing these syndromes are important in some cases of sporadic PETs (ie, nonfamilial
Tumor Biology, Prognosis, and Tumor Markers
PETs differ in their malignant potential and location (Table 1). Some PETs (insulinomas, glucagonomas, and VIPomas in adults) are found almost entirely within the pancreas, whereas others, although still referred to as PETs, actually occur in extrapancreatic locations (duodenal gastrinomas [60%–80%],30, 31, 32 small intestinal somatostatinomas [40%–50%], and growth hormone-releasing factor secreting tumor (GRFomas) primarily in the lung [>70%]) (Table 1). Insulinomas are malignant in 5%–15%,
Gastrinoma: Clinical Features/Diagnosis
Gastrinomas secrete gastrin, which causes hyperchlorhydria, thereby producing the Zollinger–Ellison syndrome (ZES).31, 45, 59, 60 With a long mean delay (6.1 y) in presentation/diagnosis,45, 61, 62 patients generally present with acid-peptic conditions including complicated and uncomplicated ulcers and/or gastroesophageal reflux disease (Table 2,top). Occasionally other manifestations such as diarrhea, malabsorption, or, in MEN1/ZES patients, various other endocrine features predominate (Table 2
Tumor Localization/Staging
Imaging studies are essential for the management of patients with PETs. They are needed to localize the primary tumor as well as for staging to guide management, including surgical plans (curative resection, debulking, or medical management only), to monitor tumor growth, and for follow-up evaluation after therapy.6, 9, 103, 104, 105, 106, 107, 108
Gastrinoma: Medical Management
In ZES acid hypersecretion is the most important clinical effect.45, 62, 167, 168 Because of their potency and long duration of action, PPIs are the agents of choice for management.31, 45, 53, 167, 169, 170 Histamine H2-receptor antagonists or SS analogues are effective, but the former drug class is limited by the need for frequent, high-dose administration,167, 169 whereas the latter class is limited by the need for parenteral therapy.
Once- or twice-daily oral PPIs (ie, omeprazole [40 mg],
Surgical Therapy for Cure
Surgery is the only treatment modality with the potential to cure patients with PETs. However, surgery is only likely to be effective in patients without diffuse metastatic disease who are able to tolerate the intervention and, in the case of ZES specifically, only in those with sporadic disease.13, 113, 197, 198, 199 Negative preoperative localization should not be considered a contraindication to surgery in patients with proven functional PETs because an experienced PET surgeon will very
General Treatment of Metastatic Disease
In recent studies the long-term outcome in patients with PETs is increasingly dependent on tumor growth. However, even with widespread liver metastases many patients remain relatively well with slow progression, especially early on in the disease process, such that many authorities advocate delaying the introduction of disease-modifying agents until there is clear development of enlarging tumor burden, or symptoms develop. Furthermore, standard antitumor therapies are not curative and
Liver-Directed Therapy (Embolization, Chemoembolization)
Most malignant PETs metastasize to the liver where they derive their blood supply from hepatic artery branches (75%–80%), in contrast to native liver tissue, which derives the majority of its blood supply from the portal vein.9, 248, 249 Recent studies have shown that liver metastases show rapid growth in less than 50% of patients and up to 30% show no growth on follow-up evaluation.33, 37, 250 Consequently, the usual approach to palliative therapy for liver metastases is to delay therapy until
Future Directions and Unsettled Problems
Even though there have been many advances in recent years in the diagnosis/management of PETs, it is not clear that survival in patients with advanced disease has improved. In fact, in a recent review294 of survival for all GI NETs (both carcinoids and PETs), no change in survival was reported over a 30-year period. Numerous factors contribute to this including their continued delay in diagnosis (mean, 4–6 y); the lack of general availability to most patients of the expertise and experience
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The authors disclose the following: this work is partially supported by the Intramural Program of the NIDDK, National Institutes of Health.