Neuroendocrine tumors (NETs) are widely distributed neoplasms described as epithelial tumors with predominantly neuroendocrine differentiation that share a common phenotype. Regardless of primary site, these tumors have a propensity to metastasize to the liver, albeit at varying rates. Historically, classification of NETs has focused more on the differences between the tumors at different sites, with names often designating the tissue of origin, such as “pancreatic islet cell” and “carcinoid” tumors. More recent classification systems, such as the World Health Organization (WHO) 2010 classification, have emphasized the greater importance of grade and differentiation with regard to prognosis, as compared with tumor location. Although there is no single classification system that includes all the various primary sites, the changes in classification reflect the general consensus that the prognosis of gastroenteropancreatic (GEP) neuroendocrine neoplasms depends more on grade and differentiation than on site. In this review, we will focus on well-differentiated nonfunctional pancreatic neuroendocrine tumors (PNETs), while mentioning the various functional tumors.
The incidence of all NETs has increased substantially, from an annual rate of 1.1 per 100,000 people in 1973 to 5.8 per 100,000 in 2008.[1,2] In our own analysis, which we performed using Yao’s method and data through 2012, the incidence appears to now approach 7 cases per 100,000 people. This increase likely reflects improved imaging and pathologic techniques as much as a true surge in the incidence of disease.
PNETs have similarly increased—to a rate of nearly 1 per 100,000 (Figure 1). PNETs make up only 7% of GEP NETs and 2% of pancreatic neoplasms.[1,3] However, PNETs account for a disproportionate number of neuroendocrine liver metastases, which are seen on presentation in an estimated 60% of patients with PNETs, compared with 27% of all patients with GEP NETs—and the lifelong incidence of liver metastases in patients with PNETs is as high as 85%.[1,2,4,5]
Several genetic syndromes are associated with NETs, including multiple endocrine neoplasia type 1 (MEN1), von Hippel–Lindau disease, neurofibromatosis type 1, and tuberous sclerosis; however, the majority of PNETs are sporadic. NETs occur in 80% to 100% of patients with MEN1, in up to 20% of patients with von Hippel–Lindau disease, in 10% of patients with neurofibromatosis type 1, and in 1% of patients with tuberous sclerosis. PNETs associated with MEN1 are often functional—for example, insulinomas and gastrinomas. Other than the rare genetic endocrinopathy, no specific recognizable cause of PNETs has been clearly identified. Less common factors associated with these tumors include smoking, diabetes, and a history of chronic pancreatitis.
NETs are often asymptomatic and are discovered incidentally. Incidentally discovered pancreatic masses now account for up to half of nonmetastatic PNETs.[7,8] The most common complaints associated with symptomatic nonfunctional PNETs include abdominal pain, weight loss, anorexia, and nausea. Less frequent complaints include jaundice, hemorrhage from tumors, and a palpable mass. Symptoms often do not appear until metastases develop.
PNETs may also present with symptoms from one of the several syndromes with which they may be associated. A synoptic description of the symptoms associated with functional syndromes is presented in Table 1. It is important to note that 70% to 90% of patients will present with nonfunctional PNETs.[9,10]
The workup of an incidental pancreatic mass or of symptoms consistent with a PNET is focused on arriving at a diagnosis, determining functionality, and delineating extent of disease. These goals are accomplished by means of cross-sectional imaging; functional imaging; invasive imaging, such as endoscopic ultrasound (EUS) or arterial stimulation venous sampling (for functional PNETs); and measurement of tumor markers.
In the workup of PNETs, cross-sectional imaging plays a major role in characterizing the primary tumor and determining the extent of disease. The sensitivity of CT and MRI for the detection of PNETs exceeds 80%, and both modalities are more sensitive than an octreotide-based scintigraphic study.[11,12] Radiologic findings suggestive of a PNET include arterial enhancement, calcifications, and occasionally necrosis or cystic degeneration. In general, CT or MRI can be used interchangeably, depending on institutional preferences.
EUS is an invaluable adjunct to CT or MRI and has superior resolution. The sensitivity of EUS alone may exceed 90%, with tumor resolution as small as 2 mm; its sensitivity approaches 100% when combined with cross-sectional imaging.[11,14] EUS is recommended when a biopsy is needed to proceed with treatment, when cross-sectional imaging does not define the pancreatic mass, or when location of the primary tumor is in question.
Functional imaging in NETs takes advantage of high levels of somatostatin receptor 2 (SSTR2) expression. It is less useful for insulinomas and poorly differentiated tumors because they often lack SSTR2.[15,16] Functional imaging can often detect primary tumors or metastatic disease not seen on cross-sectional imaging. In addition, uptake can predict response to octreotide analogs. Octreotide-based imaging is most beneficial at diagnosis and is used less frequently in surveillance.
Indium-111 (111In) pentetreotide scan (Octreoscan™) is a readily available nuclear scan that is effective at identifying nonfunctional PNETs, glucagonomas, and gastrinomas. Functional imaging has significantly improved with the recent US Food and Drug Administration (FDA) approval of gallium-68 (68Ga) DOTATATE. High-resolution positron emission tomography (PET) in combination with CT makes this imaging modality superior to 111In pentetreotide at detecting small tumors and identifying occult metastases. 68Ga DOTATATE PET/CT has a sensitivity ranging from 86% to 100% and a specificity of 79% to 100%[21-23]; what it reveals can change treatment in 20% to 55% of cases, leading to either more invasive or less invasive interventions. However, wide adoption is precluded by limited availability and high costs.
In NETs, tumor markers are useful for diagnosis, but they often play a more important role in prognostication, assessment of response to treatment, and detection of recurrence. Whereas functional PNETs can be followed with their respective secretagogues (see Table 1), as clinically indicated, nonspecific NET tumor markers, such as chromogranin A (CgA), 5-hydroxyindoleacetic acid (5-HIAA), and pancreatic polypeptide (PP), are useful in patients with nonfunctioning NETs. It is our practice to order measurements of functional markers, as well as CgA and PP, at diagnosis and to follow whichever marker is elevated. PP is less sensitive than CgA, and 5-HIAA is more useful in patients with carcinoid syndrome resulting from small bowel NETs. Given the lower utility of PP and 5-HIAA in PNETs, CgA only will be discussed in this review.
CgA is a secretory protein found in NET cells. The sensitivity and specificity of CgA in NETs are 73% and 95%, respectively. CgA is less sensitive in PNETs but still clinically useful. Elevated levels of CgA can be associated with advanced disease and predict shorter survival. CgA may be artificially low when patients are receiving somatostatin analog treatment or artificially elevated when they are receiving proton pump inhibitors or have renal failure. In cases of aberrant CgA levels, testing may be repeated with short-term follow-up.
CT and MRI, in combination with tumor markers, are the preferred modalities for surveillance and monitoring progression. Unfortunately, Response Evaluation Criteria in Solid Tumors (RECIST) may not be reliable in NETs, since tumor shrinkage is not a reliable marker of response in these patients.[28,29] In functional PNETs, the relevant functional marker is followed (see Table 1), whereas CgA or whichever tumor marker is elevated is followed in nonfunctional PNETs. Functional imaging may help to confirm recurrences observed on CT or MRI.
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