Laboratory Studies
Nonfunctioning pancreatic tumors
National Comprehensive Cancer Network (NCCN) guidelines note that patients with nonfunctioning neuroendocrine pancreatic tumors often have elevated levels of pancreatic polypeptide and chromogranin A, and those are sometimes used as biochemical markers. However, the NCCN gives such testing a category 3 rating, indicating major disagreement that the intervention is appropriate. The NCCN points out that numerous factors can lead to spurious elevations in chromogranin A levels, including impaired kidney or liver function; hypertension; chronic gastritis; and use of proton pump inhibitors, other drugs, and certain foods. [57]
However, a single-institution review of 324 patients with pancreatic endocrine tumors found that chromogranin A elevation three times the upper normal limit or more was a negative prognostic factor. [58] A study by Warner et al found that a chromogranin A ascites:serum ratio of more than 1 has excellent accuracy in predicting peritoneal metastases and/or retroperitoneal disease as the cause of ascites in patients with metastatic neuroendocrine tumors. [59]
Insulinoma
See the list below:
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Monitored fasting test: Blood is sampled to determine glucose and insulin levels every 4-6 hours and when symptoms appear. Hypoglycemic symptoms typically occur when glucose levels are less than 50 mg/dL; concurrent serum insulin levels often exceed 25 mU/mL. The diagnosis of insulinoma is additionally supported by insulin-to-glucose ratios, which are calculated at different times during the monitored fast. After a prolonged fast, healthy persons have insulin-to-glucose ratios less than 0.3, whereas patients with insulinomas typically have ratios much higher than 0.4. [12]
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Proinsulin and C-peptide test: The physiologically active form of insulin is produced in vivo when C-peptide is cleaved from proinsulin in the beta cells of the pancreas. Therefore, insulin and C-peptide are secreted in equimolar amounts, and the levels of proinsulin, C-peptide, and insulin are all increased in patients with insulinoma. The surreptitious administration of insulin should be considered when elevated insulin levels are present in a patient with normal or low proinsulin and C-peptide levels.
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Anti-insulin antibody test: The presence of serum antibodies against insulin is strongly suggestive of the surreptitious administration of insulin and not insulinoma; however, insulin antibodies, especially at high titers, may also indicate the presence of autoimmune hypoglycemia. [32]
Gastrinoma
See the list below:
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Fasting serum gastrin test: levels greater than 200 pg/mL are suggestive of gastrinoma, and levels greater than 1000 pg/mL are virtually diagnostic of gastrinoma. Serum gastrin levels are also elevated in patients with pernicious anemia because of a lack of negative feedback from parietal cell secretion of hydrochloric acid; thus, hypergastrinemia in the absence of hyperchlorhydria and peptic ulcer is not attributable to a gastrinoma.
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Gastric acid analysis: Basal acid secretion at a rate higher than 15 mEq/h or a basal-to-maximal acid output ratio that exceeds 0.6 supports the diagnosis of gastrinoma. [12]
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Secretin stimulation test: A baseline fasting serum sample is drawn, after which secretin at 2 U/kg is administered as an intravenous bolus. Blood is drawn every 5 minutes for 30 minutes, and the serum gastrin level is determined in each sample. An increase in the gastrin level of more than 200 pg/mL above the basal level supports the diagnosis of gastrinoma. [33]
VIPoma
See the list below:
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Serum VIP test: Determined during periods of ongoing diarrhea, the level of serum VIP in patients with Verner-Morrison syndrome ranges from 225-1850 pg/mL. The normal serum VIP level is less than 170 pg/mL. [60]
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Serum electrolyte analysis: Patients with WDHA syndrome generally have low serum potassium and bicarbonate levels secondary to fecal loss.
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Gastric acid analysis: Patients with WDHA syndrome have low basal gastric acid output.
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Stool analysis: VIPoma-associated diarrhea is secretory diarrhea; therefore, it has a low fecal fat content and a normal stool osmolar gap. [61]
Glucagonoma
Serum glucagon test levels greater than 1000 pg/mL are diagnostic of glucagonoma, levels less than 150 pg/mL are normal, and levels of 150-1000 pg/mL are equivocal. [48] Most patients with serum glucagon levels that are marginally elevated above 150 pg/mL do not have glucagonoma.
Somatostatinoma
With a fasting serum somatostatin evaluation, the normal level is below 100 pg/mL but patients with somatostatinoma syndrome have elevated levels on the order of nanograms per milliliter. [5, 62] This test in available only in select centers.
Imaging Studies
Practice guidelines from the National Comprehensive Cancer Network (NCCN) recommend multiphasic computed tomography (CT) or magnetic resonance imaging (MRI) studies for the evaluation of patients with neuroendocrine tumors of the pancreas. For glucagonoma, CT should be contrast enhanced. Additional imaging studies are tailored to the specific syndrome. [57]
A prospective study of gallium-68-DOTA-NOC positron emission tomography (PET)/CT of patients with gastroenteropancreatic neuroendocrine tumors demonstrated a higher sensitivity and specificity for detection of these tumors compared with other conventional imaging modalities. [63]
Computed tomography
High-resolution contrast-enhanced spiral CT scanning with thin sections (ie, 3- to 5-mm section) through the pancreas is the initial imaging technique used to localize and stage most neoplasms of the endocrine pancreas. See the images below.
Neoplasms of the endocrine pancreas. Intravenous and oral contrast-enhanced CT scan image in a patient with chronic diarrhea and elevated levels of serum vasoactive intestinal peptide. In the venous phase of this scan, the splenic vein (SV) is clearly seen draining the 5-cm tumor (T) located anteromedial to the spleen (S) in the tail of the pancreas.
Neoplasms of the endocrine pancreas. CT scan with oral and intravenous contrast in a patient with a glucagon-secreting neoplasm. This 10-cm contrast-enhancing tumor (T) is seen obliterating the normal appearance of the tail of the pancreas (Yeo, 2001).
CT scan is noninvasive; however, it fails to help identify as many as 70% of these lesions; therefore, most patients must be examined with additional, more expensive, or more invasive localization techniques. [64] The images below below are from the same patient.
Neoplasms of the endocrine pancreas. CT scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (Yeo, 1993).
Celiac axis angiography illustrating neoplasms of the endocrine pancreas. Contrast is seen opacifying the common hepatic artery (CHA) and splenic artery (SA). The superior pancreatic artery (arrow) is seen as an early U-shaped branch of the splenic artery.
Highly selective distal angiography illustrating neoplasms of the endocrine pancreas. With the arterial catheter now advanced into the superior pancreatic artery, the contrast blush of this vascular tumor is easily seen (arrows).
Magnetic resonance imaging
Significant technical advances have brought MRI to the forefront as a useful technique for the localization of neoplasms of the endocrine pancreas.
Because of the marked edema of the stromal tissue separating nests of endocrine cells, islet cell tumors present with exceptionally high relaxation times, resulting in greater enhancement on T1- and T2-weighted images than most pancreatic adenocarcinomas. Also, findings from three studies have demonstrated the usefulness of contrast-enhanced T1-weighted MRI studies in the evaluation of small primary and metastatic pancreatic endocrine tumors. [65, 66, 67] With the advent of hybrid fast-spin echo T2 sequences, small lesions that depend on minimization of motion-induced artifacts and maximization of resolution can be more accurately visualized. [68]
Somatostatin receptor scintigraphy
This novel nuclear medicine imaging modality takes advantage of the fact that pancreatic endocrine tumors, with the notable exception of somatostatinomas, express large numbers of somatostatin receptors on their cell surfaces.
Radiolabeled octreotide is a somatostatin analogue that preferentially binds to somatostatin receptors; the intravenous administration of octreotide can be used to identify such tumors. [69] See the image below.
Neoplasms of the endocrine pancreas. Octreotide scan (anterior view) in a patient with a pancreatic endocrine tumor. The large pancreatic-tail neoplasm is seen retaining tracer in the patient's left upper quadrant. Several tracer-enhancing hepatic metastases are seen in the patient's right upper quadrant and epigastrium. Tracer is also seen in the bladder following renal excretion (round density in the hypogastrium) (Yeo, 2001).
Although the limited resolution of the images from this technique does not provide the detail necessary to determine the exact location of a primary tumor, somatostatin receptor scintigraphy is particularly helpful in diagnosing small extrapancreatic metastases. [70]
Endoscopic ultrasonography
In experienced hands, transduodenal endoscopic ultrasonography (EUS) can be helpful in localizing pancreatic endocrine tumors and in assessing lymph node metastases. [71, 72]
The major disadvantage of this imaging modality is that it cannot be used to evaluate hepatic and distant spread. EUS is most useful in identifying small intraduodenal and pancreatic tumors.
The image below illustrates a hypoechoic neoplasm in a patient with an insulinoma.
Neoplasms of the endocrine pancreas. Endoscopic ultrasonography in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV) (Rosch, 1992).
Intraoperative ultrasonography
Intraoperative ultrasonography (IOUS) is the study of choice for localization of insulinomas and is more effective than any preoperative diagnostic imaging study, with a sensitivity of 90%. [73] Real-time IOUS images can provide additional information about the location and number of pancreatic endocrine tumors, and IOUS can be used to detect small lymph node and hepatic metastases. [74, 75] This technique should always be used in patients who undergo exploration for tumors that could not be definitively localized before surgery.
Provocative angiography
Because of improvements in the techniques of CT, MRI, and EUS, visceral angiography currently has no role in the selective visualization of the arterial supply to the pancreas and peripancreatic regions. [12]
Provocative angiography, as illustrated below, is a localization technique that takes advantage of the responsiveness of certain pancreatic endocrine tumors to specific biochemical stimulants and knowledge of the arterial supply of the pancreas and peripancreatic regions to map the location of occult gastrinomas and insulinomas.
Neoplasms of the endocrine pancreas. Schematic diagram of provocative angiography. Access to the central venous and arterial systems is obtained through cannulation of a femoral vein and a femoral artery. In the selective arterial secretin stimulation test, secretin is injected selectively into the splenic, gastroduodenal (a branch of the common hepatic), and inferior pancreaticoduodenal (a branch of the superior mesenteric) arteries with concomitant and subsequent hepatic venous sampling for gastrin. Based on the level of gastrin in each hepatic venous sample, the location of the gastrinoma is arterially mapped. An analogous method can be used in the selective arterial calcium stimulation test to determine the location of occult insulinomas that respond to calcium stimulation by secreting insulin.
Neoplasms of the endocrine pancreas. Graphic depiction of the results of a selective arterial secretin stimulation test in a patient with an occult gastrinoma. The gastrin gradient (the rise in hepatic vein gastrin concentration divided by the basal value) is plotted over time. An increase in gastrin gradient from 0 to 2 thus represents a 200% rise compared to the basal level. A significant rise in hepatic vein gastrin concentration is observed both after the injection of secretin into the superior mesenteric artery (SMA) and after secretin injection into the gastroduodenal artery (GDA), but no such increase occurs following secretin injection into the splenic artery (SPL). This patient's neoplasm is thus localized to the head of the pancreas or the duodenum
In the selective arterial secretin stimulation test, secretin is selectively injected into the splenic, gastroduodenal, and inferior pancreaticoduodenal arteries (the last is a branch of the superior mesenteric artery) with concomitant and subsequent hepatic venous sampling for gastrin. [76, 77] Based on the level of gastrin in each hepatic venous sample, the location of the gastrinoma is arterially mapped.
An analogous method is used in the selective arterial calcium stimulation test to determine the location of occult insulinomas, which respond to calcium stimulation by secreting insulin. [78]
Procedures
See the list below:
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Selective transhepatic portal venous sampling: This invasive test is used to help localize the tumor. In the test, blood samples are obtained from different locations within the portion of the portal venous system into which the pancreas and pancreatic bed drain. [79] Serum levels of the tumor hormone product in question are determined from the blood samples. The sample with the highest serum hormone level is presumed to have been drawn closest to the venous drainage point of the tumor and, thus, to indicate the location of the tumor.
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Endoscopy: Endoscopic evaluation of the upper gastrointestinal tract in patients with possible gastrinoma can be used to identify the location and number of peptic ulcers. The examination may reveal evidence of reflux esophagitis. Intraoperative endoscopic transduodenal illumination may be helpful in the localization of small pancreatic endocrine tumors located within the wall of the duodenum.{ref76
Histologic Findings
On light microscopy, all pancreatic endocrine tumors appear similar and resemble carcinoid tumors, the most common type of APUDomas. [18] Routine histologic examination cannot be used to predict the biologic behavior of these neoplasms. Malignancy is typically determined by the presence of tumor spread to regional lymph nodes or by the existence of hepatic or distant metastases. [12]
Immunofluorescence techniques and the peroxidase-antiperoxidase procedure allow the demonstration of specific hormones within neoplastic cells, but positive findings with immunohistochemical staining for neuroendocrine products (eg, insulin, gastrin, pancreatic polypeptide) only confirm that a particular tumor can synthesize these products; such findings provide no information about whether the synthesized products are actually being released into the bloodstream. [16]
The RUNX1T1 protein may serve as a novel biomarker for prediction of liver metastases because it is underexpressed in well-differentiated metastatic primary pancreatic endocrine tumors relative to nonmetastatic primaries. [80]
Staging
The staging system for islet cell cancer is still being developed. These tumors are most often divided into one of the following three groups:
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Islet cell cancers occurring in one site within the pancreas
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Islet cell cancers occurring in several sites within the pancreas
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Islet cell cancers that have spread to lymph nodes near the pancreas or to distant sites
Unlike pancreatic adenocarcinoma, in which the tumoral stage, resectability, and prognosis are determined by using the tumor, nodes, and metastasis classification, the prognosis of patients with pancreatic endocrine tumors is predicted on the basis of the presence or absence of liver metastases. The prognosis of patients with regional lymph node metastases is similar to that of patients with only a primary tumor. [81]
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Neoplasms of the endocrine pancreas. CT scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (Yeo, 1993).
-
Celiac axis angiography illustrating neoplasms of the endocrine pancreas. Contrast is seen opacifying the common hepatic artery (CHA) and splenic artery (SA). The superior pancreatic artery (arrow) is seen as an early U-shaped branch of the splenic artery.
-
Highly selective distal angiography illustrating neoplasms of the endocrine pancreas. With the arterial catheter now advanced into the superior pancreatic artery, the contrast blush of this vascular tumor is easily seen (arrows).
-
Neoplasms of the endocrine pancreas. Intravenous and oral contrast-enhanced CT scan image in a patient with chronic diarrhea and elevated levels of serum vasoactive intestinal peptide. In the venous phase of this scan, the splenic vein (SV) is clearly seen draining the 5-cm tumor (T) located anteromedial to the spleen (S) in the tail of the pancreas.
-
Neoplasms of the endocrine pancreas. Schematic diagram of provocative angiography. Access to the central venous and arterial systems is obtained through cannulation of a femoral vein and a femoral artery. In the selective arterial secretin stimulation test, secretin is injected selectively into the splenic, gastroduodenal (a branch of the common hepatic), and inferior pancreaticoduodenal (a branch of the superior mesenteric) arteries with concomitant and subsequent hepatic venous sampling for gastrin. Based on the level of gastrin in each hepatic venous sample, the location of the gastrinoma is arterially mapped. An analogous method can be used in the selective arterial calcium stimulation test to determine the location of occult insulinomas that respond to calcium stimulation by secreting insulin.
-
Neoplasms of the endocrine pancreas. Graphic depiction of the results of a selective arterial secretin stimulation test in a patient with an occult gastrinoma. The gastrin gradient (the rise in hepatic vein gastrin concentration divided by the basal value) is plotted over time. An increase in gastrin gradient from 0 to 2 thus represents a 200% rise compared to the basal level. A significant rise in hepatic vein gastrin concentration is observed both after the injection of secretin into the superior mesenteric artery (SMA) and after secretin injection into the gastroduodenal artery (GDA), but no such increase occurs following secretin injection into the splenic artery (SPL). This patient's neoplasm is thus localized to the head of the pancreas or the duodenum
-
Neoplasms of the endocrine pancreas. Octreotide scan (anterior view) in a patient with a pancreatic endocrine tumor. The large pancreatic-tail neoplasm is seen retaining tracer in the patient's left upper quadrant. Several tracer-enhancing hepatic metastases are seen in the patient's right upper quadrant and epigastrium. Tracer is also seen in the bladder following renal excretion (round density in the hypogastrium) (Yeo, 2001).
-
Neoplasms of the endocrine pancreas. CT scan with oral and intravenous contrast in a patient with a glucagon-secreting neoplasm. This 10-cm contrast-enhancing tumor (T) is seen obliterating the normal appearance of the tail of the pancreas (Yeo, 2001).
-
Neoplasms of the endocrine pancreas. Endoscopic ultrasonography in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV) (Rosch, 1992).
