Pancreatic neuroendocrine neoplasms: diagnosis and management
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- Balachandran, A., Tamm, E.P., Bhosale, P.R. et al. Abdom Imaging (2013) 38: 342. doi:10.1007/s00261-012-9923-1
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Pancreatic neuroendocrine neoplasms are uncommon but rising in incidence. There have been recent changes in the WHO nomenclature and a newly proposed American Joint Committee on Cancer TNM staging, which complement each other. These neoplasms are of great medical and radiological interest because of their diverse presenting features and imaging appearances. There is an increased role for both anatomic and functional imaging in the assessment of these neoplasms. A review of the nomenclature, staging, and imaging is presented in this paper.
KeywordsPancreatic neuroendocrineTNM stagingImagingCTPET–CT
Pancreatic neuroendocrine neoplasms (PNENs) are a subgroup of the gastroenteropancreatic neuroendocrine neoplasms . All gastroenteropancreatic neuroendocrine neoplasms are believed to arise from the diffuse endocrine system in the gastrointestinal tract and pancreas. These neoplasms share common markers with neural cells such as neuron-specific enolase, chromogranin, and synaptophysin .
Clinically, PNENs are divided into functional and non functional neoplasms based on hormone production and associated clinical syndrome.
PNENs were considered to be rare with an incidence of 1 per 100,000 people . However, recently the reported incidence has increased, which may be related to improved detection . PNENs have been reported to have an incidence of 2% to 10% in autopsy series [5, 6].
While older literature suggested that functional PNENs were more common, more recent literature shows that the majority of PNENs are non functional. The incidence of non functional PNENs ranges from 50% to 80% of all PNENs [7–9].
Most PNENs (both functional and nonfunctional) are sporadic and occur in adults with peak incidence between 20 and 80 years of age .
The most frequent sites of metastatic disease are liver (85%), peritoneal cavity (18%), bones (8%), other intraabdominal sites (6%), and lungs (4%) .
PNEN classification and staging
Type of neoplasms
Site of origin
Percent of malignant neoplasms
Hypoglycemia, weight gain
Throughout the pancreas
Enucleation or resection; usually no regional lymph node dissection
Peptic ulcer disease, abdominal pain, esophagitis, diarrhea
75% Gastrinoma triangle 5 times more common in the duodenum
Heterogeneous hypervascular, calcifications
Resection with regional lymph node dissection; include duodenotomy with careful search for additional tumors
Diabetes, necrolytic migratory erythema
Pancreas, mainly in the body and tail
Large and heterogeneous hypervascular, calcifications, can be cystic
Distal pancreatectomy, splenectomy, regional lymph node dissection
Watery diarrhea, hypokalemia, achlorhydria
75% Pancreas (more common in the tail) 20% neurogenic 5% duodenum
Large and heterogeneous hypervascular, calcifications
Resection with regional lymph node dissection (usually distal pancreatectomy and splenectomy)
Present with symptoms related to biliary obstruction, mass effect
60% Pancreatic head
Large and heterogeneous hypervascular, calcifications and can be cystic
Resection with regional lymph node dissection; no role for incomplete debulking
The most common functional PNENs are insulinomas and gastrinomas. Other functional PNENs are rare and include glucagonomas, VIPomas, GRFomas (Growth hormone-releasing factor).
There have been recent changes in the classification for PNENs. The WHO classification and the TNM staging classification for PNENs now complement one other.
WHO classification: comparison of WHO 2000 and WHO 2010
Well-differentiated endocrine tumor
Neuroendocrine tumor (NET) G1, G2
Well-differentiated endocrine carcinoma
Poorly differentiated endocrine carcinoma/small cell carcinoma
Neuroendocrine carcinoma (NEC) G3 small or large cell
Mixed exocrine–endocrine carcinoma (MEEC)
Mixed adenoneuroendocrine carcinoma (MANEC)
Grade of PNEN
Mitoses/10 high power fields
ENETS versus AJCC TNM classification
Confined to pancreas, <2 cm
Confined to pancreas,<2 cm
Confined to pancreas, 2–4 cm
Confined to pancreas, >2 cm
Confined to pancreas, >4 cm or invasion of the duodenum or bile duct
Peripancreatic spread but without major vascular invasion (celiac artery and superior mesenteric artery)
Invasion of adjacent organs or major vessels
Invasion of major vessels
Absence of regional node involvement
Absence of regional node involvement
Presence of regional node involvement
Presence of regional node involvement
Absence of distant metastases
Absence of distant metastases
Presence of distant metastases
Presence of distant metastases
Types of imaging
General imaging principles and technique will be discussed and imaging features for each type of PNEN will be discussed individually along with the clinical presentation of the neoplasm.
Transabdominal ultrasound is often the first imaging tool used in the patients with nonfunctional PNENs who present with jaundice. A wide range of sensitivities and specificities have been reported with both functional and nonfunctional PNENs due to operator and patient variability. The sensitivity of ultrasound improves with increasing size of the primary neoplasm .
According to a recent article , the mean detection rate for a primary PNEN by transabdominal ultrasound is 39%, ranging from 17 to 79%. Improved detection has been reported with early studies of contrast-enhanced ultrasound using harmonic microbubble-specific imaging [15, 16]. PNENs at the edge of the pancreas or close to the duodenal wall may not be well visualized . Large body habitus may also preclude effective examination of the pancreas.
Patients should be asked to drink water prior to such an ultrasound exam. The water-filled stomach can provide an anechoic window through which the pancreatic head and neck can be imaged. Decubitus positions may help to displace gastric air that may be obscuring visualization of the pancreas.
PNENs typically have the appearance of well-defined hypoechoic masses within the pancreas on transabdominal ultrasound. A well-defined hyperechoic halo may be seen. Vascularity can be demonstrated with both Doppler and contrast-enhanced techniques [15–17].
Endoscopic ultrasound (EUS)
EUS performed at the time of endoscopy utilizes a high-frequency ultrasound (7.5–10 MHz) probe placed within the stomach or the duodenum to examine the pancreas.
Limitations of EUS are its limited availability, its dependence on the skill of the operator, and its limited field of view of the abdomen which limits its role in staging.
Computed Tomography (CT)
Multiphasic multidetector (MDCT) is the cross-sectional imaging of choice at many institutions because of its ready availability, and high-spatial resolution, for detecting and staging both functional and nonfunctional PNENs.
The multiphasic MDCT imaging protocol used at our institution for PNENs includes the following: initial noncontrast images from the top of the liver to the bottom of the liver are obtained at 5 mm slice thickness and reconstructed to 2.5 mm slice thickness. A total of 125 cc of intravenous contrast is then administered at a rate of 4–5 cc per second. Using the bolus tracking function, the late arterial phase images are obtained at a 20 s delay once an enhancement threshold of 100 HU is reached in the aorta at the level of the celiac trunk. These images extend from the top of the liver to just below the iliac crests. After a subsequent delay of 15 s, the portal venous phase images are obtained from the top of the liver to just below the iliac crests. The arterial and portal venous phase images are acquired at 2.5 mm slice thickness and reconstructed to 1.25 mm slice thickness images. Delayed images through the pancreas and kidneys are obtained at a 5 mm slice-thickness reconstructed to 2.5 mm slice thickness at a 90 s delay. Use of water or volumen as negative contrast improves the detection possible concomitant lesions within bowel walls.
A consensus statement in 2009 reported a mean sensitivity and detection rate for CT of 73% (range for sensitivity 63–82%) with a specificity of 96% for PNENs . MDCT has been shown to have a high sensitivity (94%) in the detection of PNENs . Another report showed a sensitivity of 84% in the different subtypes of PNENs . The sensitivity of CT is improved with increasing size of the PNEN .
Nodal metastases tend to enhance significantly and are typically seen in the perihepatic, peripancreatic, periportal, and retroperitoneal locations.
Based on the AJCC TNM staging, evaluation of the PNEN to adjacent structures is important. Peripancreatic involvement constitutes T3 disease. If there is involvement of the celiac trunk or the superior mesenteric artery (SMA), this is considered T4 stage and in the majority of the patients, not surgically resectable.
Magnetic Resonance Imaging (MRI)
MRI is preferred over CT in the assessment of patients with a history of severe allergy to iodinated contrast material or in those with renal insufficiency. MRI is also preferred in the patients with low-grade stable metastatic disease. In patients with end-stage renal disease (in whom nephrogenic systemic fibrosis is a concern), T2-weighted sequences are superior to noncontrast CT.
Patients with PNENs undergoing MRI evaluation at our institution are imaged on either 1.5 or 3 T systems using multichannel surface coils. Patients are screened by questionnaires, and serum chemistries such as serum blood urea nitrogen (BUN), creatinine, and glomerular filtration rate (GFR) to insure they can safely undergo MRI examination. Acute renal failure and GFR levels below 30 mL/min are contraindications to gadolinium-based contrast studies at our institution.
A typical imaging protocol at our institution includes coronal fat-saturated fast imaging employing steady-state acquisition (at 5 mm slice thickness with a 0 mm skip), axial respiratory-triggered T2 fat-saturated fast spin echo (FSE) sequence (at 6 mm slice thickness with a 0 mm skip), axial T1-weighted spoiled gradient (SPGR) pre- and post-contrast (at 5 mm slice thickness with a 0 mm skip), dynamic multiphasic axial fat-saturated SPGR sequence prior to contrast administration, and at 20, 60, and 120 s post-contrast injection (at 4-mm slice thickness with a 2–2.5 mm thickness overlap), a delayed fat-saturated axial SPGR sequence at 5 min post-contrast administration (at 4-mm slice thickness with a 2–2.5 mm thickness overlap) and diffusion-weighted sequence with B values of 0 and 500. An additional axial T2 FSE sequence just through the region of the pancreas can be performed to assess the vascular structures and perivascular involvement (at 3-mm slice thickness with a 0 mm skip without fat saturation).
Studies have reported variable sensitivities and specificities for MRI. While some studies have reported superior sensitivity and specificity of 93% and 88% with MRI to CT [35, 36], other studies show comparable sensitivities to CT . However, MRI may be more sensitive than CT  in the detection of liver metastases .
PNENs show restricted diffusion. Significant differences in the ADC value have been shown between pancreatic neuroendocrine carcinomas and well-differentiated pancreatic neuroendocrine neoplasms . The ADC values have also been reported to have an inverse relation with increased cellularity of the neoplasm and Ki-67 labeling.
Somatostatin receptor scintigraphy (SRS or octreotide scan)
Somatostatin (SST) is a 14 amino acid peptide hormone present in many organs including the gastrointestinal tract and pancreas. So far five types of SST receptors have been discovered. SST has a short-biological half life of 2–4 min . A synthetic eight peptide analog called octreotide was developed and is used to bind to tissues expressing SST receptors. Octreotide has a biological half life of 1.7–1.9 h and binds primarily to tissues expressing SST receptors 2 and 5.
111In-labeled octreotide is administered at a typical dose of 5–6 mCi. The patient is then imaged with a large field of view gamma camera with SPECT (single-photon emission computed tomography). SPECT–CT is used at our institution and provides improved sensitivity and anatomic delineation over planar imaging alone. Patients are typically imaged at 4 and 24 h. Normal physiological uptake is seen in the pituitary gland, salivary glands, thyroid, liver, spleen, kidneys, and bladder.
Insulinomas express typically receptor type 3 and are therefore not often effectively evaluated on octreotide scans. Most of the other PNENs express high levels of SST subtype 2 receptors and are therefore more effectively imaged than insulinomas.
Positron emission tomography
18F-labeled FDG (fluoro deoxy glucose) PET (positron emission tomography) has been shown to be of value in patients with negative results on octreotide scan. These patients were found to have neoplasms with high Ki-67 labeling . FDG PET scan was shown to predict prognosis based on the uptake. A positive FDG-PET result was associated with a significantly higher risk of death with a hazard ratio (HR) of 10.3. Thirteen of the 57 (23%) FDG-PET-positive patients died compared with 1 of 41 (2%) FDG-PET–negative patients. In a multivariate analysis including a SUVmax of >3, Ki67, and chromogranin A, SUVmax of >3 was the only predictor of progression-free survival (HR, 8.4; P < 0.001).
At our institution, FDG-PET/CT is performed using a camera in combination with the CT component of an 8-MDCT scanner. Patients fast for at least 6 h and a blood glucose level of less than 150 mg/dL is confirmed prior to injection. Approximately 15–17 mCi of 18F-FDG is administered by an intravenous site. Imaging is performed 60–90 min after the injection with the patients positioned in the scanner in a supine position with their arms in a raised position.
Other radiotracers have been used with early promising results. A greater than 90% detection rate was shown with C11-labeled 5 hydroxy tryptophan . Another study also demonstrated a higher detection rate of 84% with C11-labeled 5 hydroxy tryptophan compared with a detection rate of 47% with SRS . 68Ga-labeled somatostatin analogs are being increasingly used in PET imaging. This is associated with higher spatial resolution and image quality when compared with octreotide scanning . A complementary role for 68Ga-labeled somatostatin analog PET imaging and 18F-FDG-PET imaging has been shown .
Insulinomas are the most common functional PNENs and are characterized by inappropriately high levels of insulin. There is a resultant hyperinsulinemic hypoglycemic state . Insulinomas are associated with symptoms of fasting hypoglycemia, documented fasting hypoglycemia with a serum glucose level less than 45 mg/dL, and the reversal of hypoglycemic symptoms with glucose administration, which constitute the Whipple’s triad. The patients may present with neuroglycopenic symptoms such as blurred vision, diplopia, confusion, and abnormal behavior from the hypoglycemia.
Insulinomas are diagnosed at the supervised fasting of these patients. A serum glucose level of < 45 mg/dL associated with a plasma insulin level of ≥3 uU/mL  is diagnostic . For patients who become symptomatic during supervised fasting, 1 mg of glucagon can be administered intravenously to reverse the hypoglycemia.
They tend to be small and uniformly hypervascular masses in the pancreas (Fig. 3A, B). When associated with MEN I (7–31% of cases) REF they can be multiple and a dedicated search to evaluate all sites of insulinomas should be made. Insulinomas are less than 2 cm in 90% of cases. They tend to be benign in a majority of cases with malignant presentation in about 10% of cases. Malignant insulinomas are uncommon and can present with liver metastases.
Surgery is the primary treatment in insulinomas. The role of preoperative imaging is to identify all the sites of insulinoma. Intraoperative ultrasound is crucial in this regard. In patients with MEN I, enucleation is the preferred method of resection due to the predisposition of these patients to multiple PNENs. Intraoperative ultrasound is useful in identifying the relationship of the insulinoma to the main pancreatic duct. Insulinomas that are close to the main pancreatic duct are at increased risk for pancreatic duct leak and hence should be managed by traditional surgery such as pancreaticoduodenectomy for neoplasms in the head of the pancreas and distal pancreatectomies for neoplasms in the tail of the pancreas. Laparoscopic operations for insulinoma are becoming more common .
The upper limit of physiologic serum gastrin level is 100 pg/mL. A fasting serum gastrin level of ≥1000 pg/mL and a gastric pH of ≤2 is diagnostic of a gastrinoma . Other causes of hypergastrinemia can confound the diagnosis. One of the most common causes is the use of proton pump inhibitors medically for symptoms of hyperacidity or reflux. Proton pump inhibitors cause hypo or achlorhydria resulting in hypergastrinemia. These medications should be stopped at least 1 week prior to testing for the presence of gastrinomas.
The most common location for gastrinomas is in the gastrinoma triangle. This is a triangle formed by the area enclosed by the junction of the cystic and common bile ducts, the second and third portions of the duodenum and the junction of the neck and body of the pancreas medially. Duodenal gastrinomas are approximately 3–10 times more common than pancreatic gastrinomas. Most of the gastrinomas are malignant.
The primary neoplasms are large, demonstrate heterogeneous enhancement and can present with lymph node and liver metastases at the time of diagnosis in 75%–80% of the cases and with bone metastases in 12% of all of the cases . The liver metastases demonstrate hypervascular and heterogeneous enhancement. The nodal metastases are typically hypervascular. Liver metastasis is the most important determinant of survival and is more common in patients with pancreatic gastrinomas rather than duodenal gastrinomas. The presence of lymph node metastases does not appear to have a significant impact on survival .
Gastrinomas are related to MEN I in 20%–60% of cases. These can be small and multiple. The overall survival of MEN I-associated gastrinomas is similar to the sporadic form and is determined by the presence of liver metastases .
In the absence of distant metastases, surgery is the treatment of choice for gastrinomas . As duodenal tumors are 3–10 times more common, a routine duodenotomy to evaluate for duodenal neoplasms and to resect these is suggested . Norton et al. showed that more gastrinomas were found in 98% of patients who had a routine duodenotomy when compared with 76% detection in patients without a duodenotomy . This was also associated with improved cure rates (52% vs. 26%). A third of patients with gastrinomas achieve long-term cure (10 years) [54, 57].
The goal of surgery is to perform a complete resection of disease. These neoplasms are more commonly treated with formal resection rather than enucleation. Routine peripancreatic lymph node dissection is also performed due to the high incidence of lymph node metastasis at the time of diagnosis.
Liver metastases are the most important prognostic factor of survival in patients with gastrinoma . Patients who were not operated on developed significantly more liver metastases than those who were operated on (29% vs. 5%) with increased mortality . Improved survival (10 year survival of 85% vs. 30%) was also demonstrated in the presence of macroscopic complete liver metastasis resection when compared with patients with incomplete or no resection . In the presence of limited metastatic disease to the liver without other sites of disease, complete resection of the metastatic disease is suggested.
In the presence of advanced metastatic disease solely to the liver, resection is suggested for symptom control is >90% of the tumor volume can be removed at surgery.
In the presence of unresectable liver metastases, liver-directed therapy such as hepatic arterial chemoembolization or bland embolization may be considered as a palliative option with response rates of 50% .
Radiofrequency ablation or cryoablation can be used in conjunction with liver surgery and is associated with less morbidity than extensive liver surgery . In patients with widely metastatic disease, chemotherapy is used. Streptozocin is approved by the FDA as a treatment for patients with PNEN. The combination of streptozocin, doxorubicin, and 5-FU in patients with locally advanced or metastatic disease was shown to have a response rate of 39% and a median survival of 37 months .
VIPomas are due to VIP (Vasoactive intestinal polypeptide) overproduction by PNENs. This results in Verner–Morrison syndrome with the triad of watery diarrhea, hypokalemia, and achlorhydria. These patients experience dehydration, hyperglycemia, and flushing .
Most VIPomas arise from the pancreas in adults but in children can arise in ganglioneuromas, ganglioneuroblastomas, and neurofibromas involving the retroperitoneum and mediastinum. Fluid and electrolyte replacement is often needed at the time of diagnosis.
An elevated VIP level (>500 pg/mL) in the presence of a secretory diarrhea is highly suggestive of a VIPoma .
They tend to be large heterogeneously enhancing masses with metastatic disease to the liver and lymph nodes at the time of diagnosis. They are of pancreatic origin in over 80% of all cases .
Glucagonomas secrete glucagon and can cause glucose intolerance, weight loss, diarrhea, migratory necrolytic erythema, and glossitis. Migratory necrolytic erythema is a skin condition characterized by erythematous macules, which become papules and heal with necrosis and pigmented scarring . Serum glucagon levels of 500–1,000 pg/mL are diagnostic of glucagonomas.
These are PNENs which are not associated with any recognizable syndrome. They are usually found incidentally or related to mass effect caused by the pancreatic neoplasm on adjacent organs. Patients can present with abdominal pain (40–60%), weight loss (25–50%), or jaundice (30–40%). They typically present with larger primary tumors and advanced disease .
They can be associated with MEN I syndrome in 80–100% of cases. In these patients, the tumors tend to be multiple in numbers.
Typically only a minority (~25%) of patients are candidates for a potentially curative resection at the time of diagnosis .
Surgical resection (pancreatic oduodenectomy or distal pancreatectomy) with lymph node dissection is indicated for resectable neoplasms without distant metastatic disease. However, only approximately 50% of those patients experience long-term cure . There is no survival benefit to incomplete resection of a primary tumor (cytoreduction or debulking) . However, for palliation of local symptoms, gastric or biliary by pass surgery could be performed. Such patients typically have a median survival of 5 years  and surgical bypass provides a more durable response than endoscopic stenting.
In the presence of metastatic disease, curative resection can be performed if all of the metastatic disease is resectable . There is no evidence that surgical resection of the primary tumor without complete resection of all metastatic disease results in increased survival . The only indication for surgery in patients with disease that cannot be completely resected is symptom palliation. Pancreatic head neoplasms can cause gastrointestinal hemorrhage from involvement of the duodenum and can cause biliary or duodenal obstruction. These can be better managed by palliative pancreaticoduodenectomy rather than bypass surgery.
The combination of streptozocin, doxorubicin, and 5-FU in patients with locally advanced or metastatic disease is used.
Temozolomide, an oral analog of dacarbazine, has also shown promising results in PNENs and is easy to administer. Temozolomide has been evaluated prospectively in combination with thalidomide, bevacizumab, or everolimus with response rates of 24–45% [73–75].
In the United States, Octreotide is the only somatostatin analog currently approved for the treatment of hormone-related symptoms from PNENs.
Decrease in neoplasm size in patients with PNENs of only 2%–3% has been demonstrated . The PROMID (Placebo-controlled, prospective randomized study on the effect of Octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine MIDgut tumors) trial showed a significant improvement in the time to progression in patients with midgut neuroendocrine neoplasms treated with Octreotide LAR. This has not been proven in PNENs .
Vascular endothelial growth factor (VEGF) inhibitor
Response of PNENs to VEGF inhibitors has been evaluated in prospective trials of patients with advanced disease. These include sunitinib and pazopanib . A phase II trial of sunitinib showed response rates of 16% in patients with advanced PNENs . Statistically significant improved progression-free survival when compared with placebo was also demonstrated.
A response rate of 17% was seen in patients on pazopanib .
Mammalian Target of Rapamycin (mTOR) inhibitors
mTOR is a serine threonine kinase which mediates tumor cell growth and controls processes such as VEGF and IGF (insulin-like growth factor)-mediated cell growth.
Temsirolimus and everolimus are rapamycin derivatives that are used in PNENs. A recent randomized study of patients with progressive advanced PNEN (RADIANT-3) was to receive treatment with everolimus or placebo. This study demonstrated significant improvement in progression-free survival with everolimus as compared to placebo (11 months vs. 4.6 months) . The overall tumor response rate associated with everolimus in this study was 5%.
Pancreatic neuroendocrine neoplasms are increasing in incidence. These encompass a wide variety of neoplasms with different presenting features. There is some controversy in the TNM staging based on the ENETS and the AJCC guidelines. Imaging is critical in evaluating the entire extent of neoplasm so as to assess for the possibility of aggressive surgical resection, which is the only curative option. New radiotracers are being used with PET–CT imaging with initial promising results. Anatomic and functional imagings are synergistic in evaluation of these neoplasms.