text:
Neoplasms of the Endocrine Pancreas
Author: Evan S Ong, MD, MS; Chief Editor: Neetu Radhakrishnan, MD
Neoplasms of the endocrine pancreas can be divided into functional and nonfunctional varieties. Most pancreatic endocrine neoplasms discovered clinically are functional—that is, they secrete one or more hormonal products into the blood, which leads to a recognizable clinical syndrome.[1]
The first report of a hormone-producing pancreatic tumor syndrome was published in 1927, when Wilder et al described insulinoma syndrome in a patient with a metastatic islet cell tumor who had hyperinsulinism and hypoglycemia.[2] Subsequently, four other classic pancreatic endocrine tumor syndromes have been described. The first is Zollinger-Ellison syndrome (also termed gastrinoma syndrome), described by Zollinger and Ellison in 1955.[3]
The second type comprises a group of three tumor syndromes: Verner-Morrison syndrome, WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, and pancreatic cholera (also termed vasoactive intestinal peptide [VIP]–releasing tumor or VIPoma); these were described by Verner and Morrison in 1958.[4]
The third is glucagonoma syndrome, described by Mallinson et al in 1974. The fourth is somatostatinoma syndrome, described by Ganda et al and Larsson et al in 1977.[5, 6]
Several other rare clinical syndromes have been proposed as possible functional endocrine syndromes associated with pancreatic neoplasms. These include the following:
Calcitoninoma [7, 8]
Parathyrinoma [9]
Growth hormone–releasing factor–secreting tumor (GRFoma)
Adrenocorticotropin hormone–secreting tumor (ACTHoma)
Neurotensinoma [10]
Patients with pancreatic neoplasms that have the histologic characteristics of a pancreatic endocrine tumor but no associated elevation in plasma hormone levels (excluding the pancreatic polypeptide level) and those without a recognizable clinical syndrome are considered to have nonfunctional pancreatic endocrine tumors. A subset of these patients have neoplasms that secrete pancreatic polypeptide (ie, PPomas). Pancreatic polypeptide (PP) is a product that appears to be a marker for pancreatic endocrine tumors, but it is not a mediator of any specific PP-related clinical syndrome.[11] Other nonfunctional pancreatic endocrine tumors likely secrete unknown products that are of little or no clinical significance.
Each of the classic pancreatic endocrine tumor syndromes is discussed in detail in the following articles:
Gastrinoma
Zollinger-Ellison Syndrome
VIPomas
WDHA Syndrome
Glucagonoma
Somatostatinomas
For discussion of other conditions with which pancreatic endocrine tumors are associated, see the following:
Multiple Endocrine Neoplasia Type 1 (MEN1)
von Hippel-Lindau Disease
The cells in pancreatic endocrine neoplasms are termed amine precursor uptake and decarboxylation (APUD) cells because they have a high amine content, are capable of amine precursor uptake, and contain an amino acid decarboxylase.[12] Pearse first used the term APUD in 1968 to unify a group of functionally and structurally similar neuroendocrine cells that are present throughout the body.[13] APUD cells were once believed to originate from the embryologic neural crest, but current evidence suggests that these cells—and thus endocrine tumors of the pancreas and other endocrine tumors of the upper gastrointestinal tract (eg, carcinoid tumors)—actually develop from the embryologic endoderm.[14]
Although the term islet cell tumor is often used to identify neoplasms of the endocrine pancreas, this is a misnomer because many pancreatic neuroendocrine tumors do not develop directly from islet cells.[15] Instead, the tumors arise from APUD stem cells, which are pluripotential neuroendocrine cells located within the ductular epithelium of the exocrine pancreas and elsewhere in the distal foregut.[16] The fact that many gastrinomas and somatostatinomas are found close to, but not within, the pancreatic parenchyma supports the notion of the possible extrapancreatic development of these neoplasms.[17]
Functional pancreatic endocrine neoplasms cause physiologic derangements related to the normal action of the hormonal product that the tumors overproduce. Thus, patients with an insulin-secreting tumor (ie, insulinoma) have the pathophysiologic manifestations of hypoglycemia; patients with a gastrin-secreting tumor (ie, gastrinoma) have hypersecretion of gastric acid, which often leads to the development of peptic ulcers (ie, Zollinger-Ellison syndrome); and so on. In contrast, patients with nonfunctional pancreatic endocrine neoplasms typically present later in the course of their disease, when their tumors begin to cause symptoms related to a mass effect.
Neoplasms of the endocrine pancreas occur in two distinct epidemiologic groups. Solitary tumors that develop in patients without a significant personal or family history of endocrine disorders are characterized as the sporadic form. The second form affects kindreds with the multiple endocrine neoplasia type 1 (MEN 1) syndrome in a pattern of autosomal dominant inheritance.[18] Approximately 80% of individuals with MEN 1 syndrome have one or more pancreatic neoplasms in their lifetime; gastrinoma and insulinoma are the most commonly identified lesions.[19]
Clinically recognized neoplasms of the endocrine pancreas are rare, with an overall annual incidence in the United States of 3-10 cases per million persons.[20, 21] However, the much higher prevalence of these tumors in unselected autopsy specimens, 0.5-1.5%, reflects the indolent nature of many of these tumors.[22, 23]
Insulinomas and gastrinomas occur with roughly equal annual incidences; together they account for more than half of all clinically apparent pancreatic endocrine tumors.[23] VIPomas are one-eighth and glucagonomas are one-seventeenth as common, whereas somatostatinomas are even more rare.[20] Nonfunctional tumors account for 14-48% of all recognized neoplasms of the endocrine pancreas.[24, 25]
Mortality/Morbidity
Functional neoplasms of the endocrine pancreas can produce the following morbidity as a result of their excess hormonal production:
If untreated, patients with insulinoma can have hypoglycemic seizures and even frank coma. [26]
Prior to the development of effective antisecretory medications (eg, histamine 2 blockers, proton pump inhibitors), patients with gastrinoma often had life-threatening gastrointestinal bleeding from peptic ulcers.
Untreated patients with VIPoma can become severely dehydrated from diarrhea, and fatal cardiac arrhythmias can develop secondary to associated hypokalemia.
Glucagonomas can cause diabetes, wasting, stomatitis, and other features similar to severe nutritional deficiency.
Late in the course of pancreatic endocrine neoplasms, the growth of the tumor can result in the following morbidity related to the mass effects of the disease:
Patients with tumors in the pancreatic head occasionally have biliary obstruction, pancreatic obstruction, or both.
Chronic abdominal pain can occur because of the compressive effects of a large intra-abdominal mass or obstructive pancreatitis.
Because of the relative rarity of pancreatic endocrine tumors in the general population, accurate rates of morbidity and mortality for persons with these lesions are difficult to determine. However, both the survival and the quality of life of patients with neoplasms of the endocrine pancreas are generally improving as a result of improvements in the modalities used to diagnose and treat these lesions (also see Prognosis).
Race-, Sex-, and Age-related Demographics
Sporadic and inherited forms of pancreatic endocrine tumors appear to occur with equal frequency among the different racial groups in the United States.
Neoplasms of the endocrine pancreas seem to have a slightly higher incidence in women than in men.[27, 18, 28] As would be expected in patients with a genetic disorder of autosomal dominant inheritance, no significant sex predilection is observed among patients with pancreatic endocrine tumors as part of MEN1 syndrome.[17]
Patients with sporadic pancreatic endocrine tumors present most commonly at the age of 30-50 years.[29] In contrast, patients with pancreatic endocrine tumors that develop as part of MEN1 syndrome tend to present when younger, commonly at age 10-30 years.[18]
The presentation in patients with neoplasms of the endocrine pancreas reflects the hormone secreted by the tumor. Thus, signs and symptoms vary with the different syndromes.
Insulinomas are insulin-secreting tumors associated with the Whipple triad. The triad includes the following[30] :
Symptoms of fasting hypoglycemia
Documented fasting hypoglycemia with a serum glucose level less than 50 mg/dL
Relief of hypoglycemic symptoms after glucose administration
Autonomous insulin secretion from insulinomas produces symptoms classified into two broad categories. Virtually all patients with an insulinoma who seek medical attention present with a subset of at least one of these two groups of symptoms, and more than half present with symptoms from both groups.[31]
First, the direct physiologic effect of hypoglycemia is neuroglycopenia, which results in the following symptoms[17] :
Visual disturbances
Obtundation, or even coma
Second, in response to neuroglycopenic stress, the body generates a compensatory state of catecholamine excess, which can lead to the following[12] :
Because insulinoma syndrome is rare and because the associated symptoms are relatively nonspecific, the physician with clinical acumen who encounters a patient with the symptoms of neuroglycopenic stress and/or catecholamine excess may think of insulinoma; however, the patient should be examined first for other more common conditions in the differential diagnosis of hypoglycemia (see Other Problems to be Considered).
Reactive hypoglycemia is the most common form of noniatrogenic hypoglycemia. Reactive hypoglycemia can be differentiated from insulinoma syndrome by a history of symptom onset 3-4 hours after meals, rather than after extended periods of fasting.[32]
The classic triad of Zollinger-Ellison syndrome includes the following[3] :
Severe gastrointestinal ulcerative disease
Gastric acid hypersecretion
Non-beta islet cell tumors of the pancreas
Zollinger and Ellison rightly proposed that these pancreatic tumors released a stimulatory secretagogue into the circulation that induced gastric acid hypersecretion, resulting in ulcer disease. This substance is the polypeptide hormone now called gastrin. Currently, one patient in 1000 with primary duodenal ulcer disease and two patients in 100 with recurrent ulcers after ulcer surgery are estimated to have a gastrinoma.[33]
The clinical symptoms of patients with gastrinoma are a direct result of excessive levels of circulating gastrin. Abdominal pain and peptic ulceration of the upper gastrointestinal tract are the most common symptoms and are observed in 90-95% of patients with Zollinger-Ellison syndrome.[34, 35]
Peptic ulcer symptoms in patients found to have gastrinomas are similar to those of patients with a common peptic ulcer. The symptoms may be more protracted than those of a common peptic ulcer, and they are frequently refractory to standard medical and surgical therapies.
Although the symptoms of gastroesophageal reflux disease are rarely the only symptoms, they occur in approximately one third of the patients with Zollinger-Ellison syndrome. As many as 60% of patients with Zollinger-Ellison syndrome report dysphagia or odynophagia or have endoscopic findings consistent with reflux esophagitis.[36, 37]
Diarrhea occurs in more than a third of patients with gastrinoma; it is secondary to both the high volume of hydrochloric acid in the upper gastrointestinal tract and the direct effects of circulating gastrin on the secretory and absorptive properties of the small intestine. Occasionally, diarrhea may be the only presenting symptom of a gastrinoma.[38, 39]
Steatorrhea occurs in some people with gastrinoma syndrome secondarily; acid in the duodenum and proximal jejunum irreversibly denatures the pancreatic lipase, inactivating it. The denatured lipase is unable to hydrolyze intraluminal triglycerides to their respective diglycerides, monoglycerides, and fatty acids for absorption.[40]
Because the clinical history of patients with Zollinger-Ellison syndrome is often indistinguishable from that of patients with ordinary peptic ulcers, certain clinical conditions should alert clinicians to the possibility of gastrinoma syndrome. Many consider the following conditions to be indications for the initial measurement of a serum gastrin level[12] :
Postbulbar ulcers
Multiple ulcers
Ulcers refractory to standard medical therapy
Ulcer recurrence after antiulcer surgery
Ulcer and diarrhea
Prolonged unexplained diarrhea
Family history of peptic ulcer
Family history suggestive of MEN 1syndrome
Ulcers in patients who are negative for Helicobacter pylori infection and have no history of nonsteroidal anti-inflammatory drug (NSAID) use
Nongastrinoma pancreatic endocrine tumor (ie, because of the high association of secondary elevations in hormone levels) [41, 42]
Prominent gastric rugal folds on images from upper endoscopy or a gastrointestinal series (reflecting the trophic effect of gastrin on the gastric fundus)
VIPoma
Symptoms of Verner-Morrison or WDHA syndrome (ie, watery diarrhea, hypokalemia, achlorhydria, acidosis) are the result of the physiologic effects of overproduction of VIP by pancreatic endocrine neoplasms.
The primary and ubiquitous symptom of patients with a VIPoma is watery diarrhea, the occurrence of which may be constant, episodic, or intermittent.[23] Because diarrhea production in persons with Verner-Morrison syndrome is due to cyclic adenosine monophosphate–mediated prosecretory gastrointestinal stimulation by VIP, the term pancreatic cholera has been used to emphasize the physiologic mechanism of this disease.[17]
Abdominal cramps are common among patients with VIPoma syndrome, and flushing episodes occur in a small percentage of patients.[43]
The remaining symptoms associated with VIPomas are secondary to hypokalemia, which occurs because of fecal potassium losses that can reach 400 mEq/d. These symptoms may include muscular weakness, lethargy, and nausea.[12]
Glucagonomas secrete excessive amounts of glucagon and cause a syndrome characterized by the following[44] :
The dermatitis associated with glucagonoma syndrome is termed necrolytic migratory erythema. This dermatitis is characterized by the cyclic migration of erythematous patches that spread serpiginously and then reveal central points of healing.[45]
Hyperglucagonemia in patients with glucagonomas results in glucose intolerance (ie, diabetes) and cachexia (secondary to anorexia and the catabolic effects of glucagon) that can be significant, even when the tumors are small and not metastatic.[46]
In addition, as many as a third of patients with glucagonoma syndrome have secondary thromboembolic phenomena; therefore, they may have a history consistent with deep venous thrombosis and/or pulmonary embolism.[47] This feature of glucagonomas is unique among the different neoplasms of the endocrine pancreas.
Normochromic normocytic anemia occurs in approximately half the patients with glucagonoma, and may manifest as fatigue.[48]
Somatostatinoma
The symptoms of somatostatinoma syndrome reflect the general inhibitory action of somatostatin on global gastroenteropancreatic function, as follows:
Patients with somatostatinomas often have history findings consistent with diabetes mellitus, which is probably secondary to the inhibitory action of somatostatin on insulin and glucagon release[49]
Inhibition of the action of cholecystokinin by somatostatin[50] likely causes relative biliary stasis and the formation of gallbladder calculi; this inhibition may be responsible for the symptoms of biliary colic that often occur in patients with somatostatinomas[51]
Patients with somatostatinoma syndrome may also have diarrhea and/or steatorrhea, both of which are likely to be caused by the inhibition of pancreatic enzyme and bicarbonate secretion[23]
When examining patients who present with the aforementioned features, the astute clinician should keep in mind that the triad of hyperglycemia, gallstones, and steatorrhea is not specific for somatostatinoma syndrome. Therefore, patients with these findings should be examined for more common disease entities prior to a comprehensive workup for somatostatinoma.
Carcinoid tumor
The signs and symptoms of carcinoid tumor are related to hypersecretion of serotonin (5-HT) and include the following:
Heart valvular lesions
Additional functional tumors of the endocrine pancreas have been reported, with secretion of growth hormone–releasing factor (GRF), neurotensin, parathyroid hormone-related peptide, pancreatic polypeptide (PP), adrenocorticotropin hormone (ACTH), and melanocyte-stimulating hormone (MSH), as follows:.
ACTHomas cause Cushing syndrome, with manifestations that include facial and torso obesity, high blood pressure, stretch marks on the abdomen, generalized weakness, osteoporosis, and facial hair growth in females
MSHomas cause skin hyperpigmentation
GRFomas primarily result in acromegaly but can also present as other symptoms; they are frequently associated with MEN 1 syndrome and can be accompanied by Zollinger-Ellison syndrome and/or Cushing syndrome in 40% of the cases
Neurotensinomas can cause hypotension, hypokalemia, weight loss, flushing, and diabetes; these tumors are usually malignant
PPomas have no characteristic symptoms and are associated with high circulating PP levels, although high PP levels can also be seen with other islet cell tumor syndromes
Physical examination in patients with pancreatic endocrine tumors generally reveals nonspecific findings. However, visual identification of glucagonoma-associated necrolytic migratory erythema, stomatitis, angular chelitis, and VIPoma-associated flushing are important diagnostic clues.
Patients with functional neoplasms of the endocrine pancreas usually present when their tumors are small; however, a mass may be found on abdominal palpation if the patient has a large, nonfunctional tumor.
Large, nonfunctional neoplasms in the head of the pancreas may occasionally cause biliary obstruction, which can lead to jaundice.
Fundamental understanding of pancreatic endocrine tumors has increased greatly because of recent observations in the fields of classic and molecular genetics, as follows:
In one small series of malignant pancreatic endocrine tumors analyzed by genetic karyotyping, clonal chromosomal abnormalities were identified in more than half the specimens.[52]
Amplification of the HER-2/neu proto-oncogene has been demonstrated in gastrinomas (Evers, 1994), and a high level of mRNA expression for the alpha subunit of the cell cycle protein Gs is observed in insulinomas.[53]
Loss of heterozygosity at band 11q13 that results in the inactivation of a tumor suppressor gene in this region has been demonstrated in sporadic pancreatic endocrine tumors and in tumors of patients with MEN 1 syndrome or of those with von Hippel-Lindau syndrome.[54]
Recent genetic studies of endocrine tumors of the pancreas have suggested novel loci for tumor suppressor genes 3p25, 3p27, and 11p13, and others. Loss of alleles in these regions may serve as markers for malignant endocrine tumors of the pancreas. Also recently demonstrated is the fact that cyclin-dependent kinase inhibitor, p27kip1, is abundantly present in well-differentiated tumors but scant or absent in more aggressive tumors.
Multiple endocrine neoplasia type 1 (MEN 1) syndrome
MEN 1 syndrome, Wermer syndrome, is a genetic disorder with an autosomal dominant pattern of inheritance. The syndrome is characterized by hyperparathyroidism, adenomas of the pituitary, and neoplasms of the endocrine pancreas.[55]
As many as 97% of patients with MEN 1 syndrome have hyperparathyroidism. Between one third and one half of patients with MEN 1 syndrome have pituitary adenomas; prolactin-secreting tumors are the most common type.
Approximately 80% of patients with MEN 1 syndrome have pancreatic endocrine neoplasms. The pancreatic tumors in these patients tend to be multiple and usually secrete multiple hormonally active products.
Nearly all patients with pancreatic endocrine tumors associated with MEN 1 syndrome have one or more nonfunctional lesions, and the majority also have functional neoplasms, including gastrinomas (54%), insulinomas (21%), glucagonomas (3%), and VIPomas (1%).[23]
No well-established environmental factors are known to be associated with the development of neoplasms of the endocrine pancreas. This lack is in stark contrast to knowledge about the development of neoplasms in the exocrine pancreas, for which cigarette smoking, specific diets, and exposure to industrial toxins are known risk factors.[56]
The differential diagnosis (DDX) of hypoglycemia includes the following[12] :
Reactive hypoglycemia
Functional hypoglycemia associated with gastrectomy or gastroenterostomy
Nonpancreatic tumors
Adrenal carcinoma, hepatocellular carcinoma, carcinoid, hypopituitarism, chronic adrenal insufficiency, extensive hepatic insufficiency, and surreptitious self-administration of insulin or ingestion of oral hypoglycemic agents. [12]
See the review article by Service for an exhaustive list.[32]
The DDX of peptic ulcer includes Helicobacter pylori infection, NSAID use, gastric cancer, duodenal cancer, pancreatic cancer, ischemic gastric injury, and postoperative marginal ulcer.
The DDX of hypergastrinemia due to nonulcerogenic causes (ie, with normal-to-low acid secretion) includes atrophic gastritis, pernicious anemia, previous vagotomy, renal failure, and short-gut syndrome.[12]
The DDX of hypergastrinemia due to ulcerogenic causes (ie, with excessive acid secretion) includes antral G cell hyperplasia or hyperfunction, gastric outlet obstruction, retained excluded antrum, and Zollinger-Ellison syndrome.[12]
The DDX of watery diarrhea includes villous adenoma, laxative abuse, celiac disease, parasitic and infectious diseases, inflammatory bowel disease, carcinoid syndrome, and gastrinoma.[12]
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]
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]
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.
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]
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.
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]
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]
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]
Serum electrolyte analysis: Patients with WDHA syndrome generally have low serum potassium and bicarbonate levels secondary to fecal loss.
Gastric acid analysis: Patients with WDHA syndrome have low basal gastric acid output.
Stool analysis: VIPoma-associated diarrhea is secretory diarrhea; therefore, it has a low fecal fat content and a normal stool osmolar gap.[61]
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.
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]
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).
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]
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.
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
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]
The staging system for islet cell cancer is still being developed. These tumors are most often divided into one of the following three groups:
Islet cell cancers occurring in one site within the pancreas
Islet cell cancers occurring in several sites within the pancreas
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]
Treatment must be individualized in patients with a neoplasm of the endocrine pancreas, in order to balance management of the effects of hormone production with management of the symptoms related to the bulk of the tumor.[82] Many pancreatic endocrine tumor syndromes are potentially life-threatening upon presentation; therefore, initial medical therapy is aimed at stabilizing the patient sufficiently to permit a complete preoperative evaluation.[17]
The only effective medication for functional pancreatic endocrine neoplasms in general is a long-acting somatostatin analog (eg, octreotide). Somatostatin analog treatment can improve symptoms and quality of life in all the functional pancreatic endocrine neoplasms except somatostatinoma.[83]
Although octreotide-long-acting repeatable (LAR) is approved for use at doses of up to 30 mg every 4 weeks, a systematic review by Broder et al found multiple studies in which expert clinical opinion supported dose escalation to up to 60 mg monthly for symptom control in patients with neuroendocrine tumors and suggested that higher doses may be effective at preventing tumor progression.[84]
Al-Efraij et al reported that dose escalation of octreotide-LAR was associated with improved symptom control in neuroendocrine tumor patients whose symptoms were refractory to standard doses. However, they found that levels of the tumor markers chromogranin A (CGA) and 24-hour urinary 5-hydoxyindoacetate (5-HIAA) showed variable response to octreotide-LAR dose escalation, so measurement of those biomarkers may not provide an accurate assessment of therapeutic efficacy.[85]
Aside from somatostatin analog therapy, the specific treatment for each syndrome depends on the action of the particular hormone product secreted.[86] The use of specific pharmacologic agents (including chemotherapeutic agents) in the treatment of patients with endocrine neoplasms of the pancreas is discussed in Medication.
Lutetium Lu 177-dota-tate (Lu 177), the first peptide receptor radionuclide therapy (PRRT), was approved by the US Food and Drug Administration (FDA) in 2018. Approval was based on the NETTER-1 clinical trial, a single-institution, single-arm, open-label trial in more than 1,200 patients with somatostatin receptor–positive tumors. Results showed a 79% reduction in risk of disease progression or death in the Lu 177 arm compared with octreotide LAR 60 mg arm (95% CI: 0.13-0.32; p< 0.0001). Median progression-free survival (PFS) was not reached in the Lu 177 arm, compared with 8.5 months for octreotide LAR. An interim overall survival analysis determined that Lu 177 treatment led to a 48% reduction in the estimated risk of death (hazard ratio 0.52, 95% confidence interval [CI]: 0.32-0.84) compared with octreotide LAR.[87]
Chenk et al reported that therapy with long-acting somatostatin analogs decreases radioiosotope uptake in the thyroid, spleen, and liver on radiolabeled octreotide scintigraphy, but in most cases increases intensity of uptake within metastases. These authors suggest that pretreatment with somatostatin analogs before performing PRRT may enable delivery of higher doses to tumor while decreasing the dose to normal tissues.[88]
A study by Yao et al found that everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), significantly prolonged progression-free survival in parents with progressive advanced pancreatic neuroendocrine tumors when compared with placebo. It was associated with a low rate of severe adverse affects.[89]
A study by Raymond et al found that continuous daily administration of the multikinase inhibitor sunitinib (37.5 mg) improved PFS, overall survival, and objective response rate in patients with advanced pancreatic neuroendocrine tumors, compared with placebo.[90]
A retrospective chart review by Anthony et al looked at patients with pancreatic neuroendocrine tumors with and without carcinoid syndrome and their response to treatment with octreotide LAR.[91] Approximately 57% of patients demonstrated stable disease on octreotide LAR (dose range, 20-60 mg). Although this is a cancer not frequently seen in general endocrinology practice, its management with octreotide LAR is a helpful finding.
In a phase II study of 58 patients with well or moderately differentiated pancreatic neuroendocrine tumors, the response rate to combination treatment with the mTOR inhibitor temsirolimus and the vascular endothelial growth factor (VEGF)-A monoclonal antibody bevacizumab was 41%. At 6 months, the PFS rate was 79%. Median PFS was 13.2 months, and median overall survival was 34 months. The most common treatment-related adverse events were hypertension, fatigue, lymphopenia, and hyperglycemia.[92]
Combination treatment with bevacizumab and streptozocin plus 5-fluorouracil (5-FU) in an open-label study of 34 patients with progressive, metastatic, well-differentiated pancreatic neuroendocrine tumors resulted in median PFS of 23.7 months after a maximum of 24 months of follow-up. A partial response was seen in 19 (56%) patients, and 15 (44%) patients had stable disease. Overall survival at 24 months was 88%. The most common adverse events were hypertension, abdominal pain, and thromboembolism.[93]
Treatments for specific syndromes may include the following:
Insulinoma - Upon initial presentation, patients with insulinoma may require immediate potassium replacement and dextrose administration. Hypoglycemia can often be managed in the preoperative period by administering diazoxide, which inhibits insulin release from both normal beta cells and insulinoma cells.[94, 31]
Gastrinoma - The two main goals in the initial treatment of a patient with a gastrinoma are (1) to stabilize the general hemodynamic condition of the patient and control bleeding from gastrointestinal ulcers and (2) to establish a nonacidic gastric pH with the use of proton pump inhibitors (eg, omeprazole).[12]
VIPoma - The primary initial concern in the treatment of a patient who presents first with VIPoma-associated diarrhea is the replacement of volume losses and the correction of acid-base and electrolyte abnormalities.[43]
Glucagonoma - Patients with glucagonomas generally have nutritional depletion and often require blood transfusions, total parenteral nutrition, and preoperative control of hyperglycemia.[17]
Somatostatinoma - Nutritional repletion and control of hyperglycemia are important aspects of good medical care in patients with somatostatinoma syndrome.
Extralymphatic metastatic spread of pancreatic endocrine neoplasms primarily involves the liver. Therefore, cytoreductive techniques that lower serum levels of the offending gastroenteropancreatic hormone by decreasing hepatic tumor bulk often improve the patient's quality of life. Similar to surgical resection of hepatic metastases (discussed below), hepatic arterial embolization with or without chemotherapy yields impressive results in terms of tumor, hormone, and symptom regression.[95] Cryosurgery is reported to ameliorate symptoms in patients with hepatic metastases that are resistant to chemotherapy,[96] and the successful treatment of these lesions with radiofrequency ablation has also been reported.[97]
Practice guidelines from the National Comprehensive Cancer Network recommend that patients being considered for surgery with possible splenectomy (eg, for treatment of glucagonoma) receive trivalent vaccine (ie, pneumococcus, Haemophilus influenzae type b, and meningococcus group C).[57]
At the time of surgical exploration for pancreatic endocrine neoplasms, the pancreas and peripancreatic regions are completely evaluated. Dividing the gastrocolic ligament exposes the body and tail of the pancreas. This portion of the pancreas can be partially elevated out of the retroperitoneum by dividing the inferior retroperitoneal attachments to the gland. After the second portion of the duodenum is elevated out of the retroperitoneum by means of the Kocher maneuver, the pancreatic head and uncinate process are palpated bimanually. The liver is carefully assessed for evidence of metastatic disease. Potential extrapancreatic sites of tumoral involvement are evaluated in all cases, with particular attention to the duodenum; splenic hilum; small intestine and its mesentery; peripancreatic lymph nodes; and, in women, the reproductive tract.[12]
The goals of surgical therapy for pancreatic endocrine neoplasms include (1) controlling the symptoms of hormone excess, (2) safely resecting the maximal amount of tumor mass possible, and (3) preserving the maximal amount of pancreatic parenchyma possible.[12] Surgical management of the primary tumor is similar for the different types of pancreatic endocrine neoplasms. Surgical treatments may include the following:
Small benign lesions remote from the main pancreatic duct can be enucleated.[27, 12]
Tumors deep in the substance of the pancreatic gland, and therefore close to the main duct, have ill-defined capsules, and tumors larger than 2 cm in diameter should be treated with regional pancreatectomy.
Tumors in the body or tail of the pancreas can be managed with distal pancreatectomy.[98]
Lesions in the head or uncinate process of the pancreas can be resected with pancreaticoduodenectomy.[99, 100]
Tumors in the neck of the pancreas can now be managed with middle-segment pancreatectomy by oversewing the proximal pancreatic stump and draining the distal pancreatic duct via a pancreaticogastrostomy or pancreaticojejunostomy.
When a preoperatively occult gastrinoma is not found during surgical exploration, despite the use of intraoperative ultrasonography and endoscopic transduodenal illumination, longitudinal duodenotomy can be performed at the level of the second portion of the duodenum to allow eversion of the duodenum to assess for duodenal microgastrinomas.[101] Then, the localized microgastrinomas can be resected and the duodenal defect closed.[102]
Rather than performing a blind regional pancreatectomy for an occult insulinoma or gastrinoma, selective provocative angiography (see Workup/Imaging Studies) should be performed so that the appropriate pancreatic segment can be resected, eg, distal pancreatectomy versus pancreaticoduodenectomy.[28]
Metastatic disease to the liver should be resected when possible.[103] In patients with unresectable disease, radiofrequency or cryosurgical ablation should be considered.[104]
In the past, most patients with metastatic neoplasms of the endocrine pancreas died of the hormone-excess states, but with the development of increasingly effective medical therapies to control this pathophysiologic condition (ie, proton pump inhibitors for gastrinomas; octreotide for other endocrine tumors), the major determinant of long-term patient survival is becoming the malignant nature of the tumors. For this reason, hepatic metastases are debulked with cytoreductive surgical resection. However, most surgeons believe that this aggressive approach should be reserved for patients in whom near 100% tumor removal can be achieved with reasonable safety.[105]
In a study of survival data of 882 patients with metastatic nonfunctioning pancreatic neuroendocrine tumors (NFpNET), resection of the site of the primary NFpNET was associated with greater survival of 65 (95% confidence interval 60-86) versus 10 (8-12) months for those without resection (P < 0.0001).[106]
Pancreatic or oncologic surgeon
Dietary considerations in patients with functional endocrine pancreas neoplasms include the following:
Patients with unresectable insulinoma may gain some symptomatic relief by eating frequent small meals with a high starch and complex carbohydrate content. [31]
In contrast to the symptoms of routine dyspepsia, diet modification rarely ameliorates the symptoms or complications of gastrinoma-associated hyperchlorhydria.
Patients with VIPomas, glucagonomas, and somatostatinomas frequently have fluid, electrolyte, and nutritional deficits, and they often require parenteral supplementation. [17]
Exercise often exacerbates the symptoms of insulinoma syndrome secondary to relative substrate deficiency such as hypoglycemia.[107] Therefore, patients with insulinoma may need to avoid exercise until their tumor is successfully resected.
Guidelines Summary
Practice guidelines from the National Comprehensive Cancer Network (NCCN) recommend resection as the primary treatment for locoregional disease. Patients with other life-limiting co-morbidities or high surgical risk should be excluded, particularly when tumors are small and indolent. Additional recommendation include the following[57] :
Incidental nonfunctional local tumors ≤1 cm - In selected cases, observation alone is an option.
Nonfunctional tumors 1-2 cm in size - Resection of lymph nodes should be considered.
Large (> 2 cm) node-positive nonfunctional tumors - Resection should involve removal of the tumor with negative margins (including adjacent organs) and regional lymph nodes.
Occult gastrinoma - Observation or exploratory surgery are options.
Gastrinomas in the duodenum require duodenotomy and intraoperative ultrasound with local resection or enucleation and periduodenial node dissection.
Gastrinomas in the distal pancreas - Distal pancreatectomy is indicated.
Insulinomas - The primary treatment is enucleation.
Glucagonomas - Treatment is distal pancreatectomy with splenectomy and peripancreatic lymph node resection.
The goals of palliative medical therapy for pancreatic endocrine neoplasms are (1) the reduction of symptoms related to hormonal excess and (2) the control of tumor cell proliferation.
Antisecretory agents
Used to modulate the release of gastroenteropancreatic hormones from both normal and neoplastic APUD cells in the treatment of pancreatic endocrine tumor syndromes to reduce specific symptoms related to hormonal excess.
Octreotide (Sandostatin)
Somatostatin analogue that binds somatostatin receptors on pancreatic endocrine tumor cells and inhibits release of many gastroenteropancreatic hormones.
Useful adjunct in palliative treatment of patients with most functional metastatic pancreatic endocrine tumors. Evidence suggests that it may also have antiproliferative effects in rare cases. However, symptomatic and antiproliferative effects last only months and are probably of short duration secondary to down-regulation of cell-surface somatostatin receptors (Maton, 1989). Because octreotide is a somatostatin agonist, it is not useful in the treatment of patients with somatostatinoma syndrome (Pless, 1986). Doses of 300-600 mcg/d or higher seldom result in additional biochemical benefit.
Radiolabeled somatostatin analog binds to somatostatin receptor-expressing cells.
Lutetium Lu 177-dota-tate (Lutathera)
Binds to somatostatin receptors with highest affinity for subtype 2 receptors (SSRT2). Upon binding to somatostatin receptor-expressing cells, including malignant somatostatin receptor-positive tumors, the compound is internalized. Beta emission from Lu 177 induces cellular damage by forming free radicals in somatostatin receptor-positive cells and in neighboring cells. It is indicated for somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.
Immunotherapeutics
Used to modulate host immune responses to neoplastic cells. Control of tumor cell proliferation is the goal when these agents are used to treat patients with pancreatic endocrine tumor syndromes.
Interferon alfa-2a (Roferon-A) and alfa-2b (Intron A)
Protein product manufactured by using recombinant DNA technology.
Pancreatic endocrine tumor patients treated with human leukocyte interferon have objective response rates of 77%, with effects lasting > 1 year in some cases.
Responses represent primarily decreased hormone production rather than objective reduction in tumor bulk (Oberg, 1989). Mechanisms of hormone reduction and antitumor activity are not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response likely have important roles.
Chemotherapeutics
Primarily reserved for patients with pancreatic endocrine neoplasms that are metastatic and/or unresectable.
While most experts agree that chemotherapy is indicated in patients who have symptoms from tumor bulk or uncontrolled syndromes of hormone excess that cannot be palliated with other means (eg, cytoreductive surgery, cryosurgery, radiofrequency ablation, hepatic artery embolization), no consensus exists on when therapy should be started in asymptomatic patients with metastatic or recurrent disease. One common practice is to reassess patients at 3- to 6-month intervals after diagnosis of metastatic or recurrent disease. Patients with clear tumoral progression are treated with chemotherapy, whereas those with stable lesions are monitored. No benefit from chemotherapy has been demonstrated in patients with metastases to only lymph nodes.
Studies of patients with advanced islet cell carcinomas in which streptozocin alone was compared with streptozocin plus 5-fluorouracil (5-FU) have overall response rates as high as 63%, and survival rates increased by as much as 1 year with combination therapy, although single-agent therapies have generally yielded lower response rates.[108] A study of streptozocin plus doxorubicin compared with streptozocin plus 5-FU revealed a better response rate of 69% and an increased survival rate for patients treated with streptozocin plus doxorubicin.[109] Use of liposomal doxorubicin markedly reduces the risk of cardiac toxicity with this regimen, while efficacy remains comparable.[110] In a study of patients with all types of GI neuroendocrine tumors, streptozocin was found to be more effective in patients with islet cell tumors than in those with carcinoid tumors.[95] However, a small study of patients with islet cell carcinomas treated with the combination of streptozocin, doxorubicin,and 5-FU had a response rate of only 54% and no complete responses.[111]
A number of other chemotherapeutic drugs, such as the taxanes, platinum compounds, gemcitabine, camptothecin analogues, targeted receptor antagonists, and antiangiogenesis/antiendothelial agents, have demonstrated activity against pancreatic endocrine tumors, but none has been adequately evaluated in these neoplasms or has demonstrated results as good as those of various combinations of streptozocin, doxorubicin, and 5-FU.[82]
Streptozocin (Zanosar)
Has diabetogenic action in some animals that is correlated with selective uptake of the drug by pancreatic beta cells (Schein, 1973). As a result, streptozocin is uniquely helpful in the treatment of insulinoma. Also inhibits cell proliferation and is cytolytic. Interferes with normal DNA function by means of alkylation and protein modification.
Doxorubicin (Adriamycin, Rubex)
Inhibits topoisomerase II and produces free radicals that may destroy DNA. Combination of these events can inhibit growth of neoplastic cells.
Fluorouracil (Adrucil)
Fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase and interferes with RNA synthesis and function. Has some effect on DNA.
Further Outpatient Care
Patients who have undergone surgical resection of neoplasms of the endocrine pancreas require close follow-up with an endocrinologist or medical oncologist, and surveillance serum hormone levels should be tested regularly to ensure that recurrence is diagnosed early and treated appropriately.
Adjuvant radiotherapy after surgery might aid local control, according to one retrospective study. Patients who received radiotherapy had high long-term survival rates and similarly low rates of recurrence compared to patients who did not undergo radiotherapy. However, patients who received radiotherapy were more likely to have larger tumors and node positivity.[112]
Proper outpatient treatment of patients with unresectable pancreatic endocrine tumors requires regular follow-up with endocrinologists and medical oncologists.
Further Inpatient Care
Patients who have complications from chemotherapy (eg, myelosuppression, kidney failure, liver failure, severe gastrointestinal toxicity) may require inpatient treatment.
Patients with tumor recurrences that lead to the recurrence of symptomatic hormone-excess states may again require inpatient care to correct fluid, electrolyte, and nutritional disturbances.
Inpatient & Outpatient Medications
Interferon and cytotoxic chemotherapeutic agents are generally administered in a well-controlled outpatient or inpatient setting.
Patients can also consider enrollment in a clinical trial, such as those listed on the National Institutes of Health ClinicalTrials.gov Web site.
Neoplasms of the endocrine pancreas are rare, their diagnosis and localization often require advanced technologies, and their successful treatment requires a careful multidisciplinary approach. For those reasons, patients with a possible or confirmed pancreatic endocrine tumor are best treated at a large referral center where endocrinologists, gastroenterologists, pancreatic surgeons, and medical oncologists are available.
A study of 125 patients who underwent surgical resection of pancreatic neuroendocrine tumors between 1949 and 1996 had complications that included pancreatic fistula (16%), wound infection (15%), delayed gastric emptying (8%), and death (2.8%)[25] :
Extended resection for pancreatic tumors can result in permanent diabetes mellitus.
Complications of medical therapies are discussed in Medication.
Endocrine tumors of the pancreas typically have indolent growth. Nevertheless, the rate of tumor growth is still a major determinant of survival in patients with these lesions.[17]
Because these tumors usually grow slowly and have a relatively low metastatic potential and because no specific criteria have been defined to predict their behavior, the distinction between benign and malignant neoplasms is based on the presence of metastatic disease; therefore, long-term clinical follow-up is often required.[18, 29]
Neoplasms of the endocrine pancreas have patterns of initial tumor spread that are similar to those of other gastrointestinal carcinomas, as follows:
The neoplasms spread first to regional lymph nodes and then to the liver
Bone metastases may occur late in the course of the disease and indicate a poor prognosis[15]
In rare cases, pancreatic endocrine tumors metastasize to the lungs or brain
Currently, the most important prognostic factor that determines the survival of patients with neoplasms of the endocrine pancreas is the presence or absence of metastatic disease.
Because even metastatic pancreatic endocrine neoplasms typically grow slowly, the prognosis in patients with these tumors is relatively good compared with that in patients with nonendocrine pancreatic cancers.
More than 90% of patients with insulinomas have benign neoplasms without evidence of metastases, and as many as 97% of these patients can be cured with surgical resection.[113]
Patients with gastrinomas have a poorer prognosis; 60% of these tumors are malignant.[114] However, survival rates are strikingly different between patients in whom gastrinoma metastasis is limited to the lymph nodes and those with hepatic metastases, as follows:
Patients in whom gastrinoma metastasis involves only the lymph nodes can live a quarter decade or longer, and their life expectancy is indistinguishable from that of patients with gastrinoma in whom no tumor is identified at surgery.[115, 116, 117]
Patients with hepatic gastrinoma metastases have a 5-year survival rate of 20-30%, compared with approximately 90% in patients without liver metastasis.[118]
Among pancreatic endocrine tumors, glucagonomas tend to be relatively large (5-10 cm) at diagnosis. Also, as many as 80% are invasive or metastatic; this frequency rate is higher than that of the other tumors.[47, 46, 119] Because glucagonoma syndrome is recognized relatively late in most patients, surgical cure is likely in fewer than 20% of all patients.[23]
Approximately half of all VIPomas are metastatic at the time of diagnosis or surgery,[23] and approximately one third of patients are cured with surgery.[120, 121]
Most somatostatinomas (84%) are metastatic at the time of presentation, but a number of patients survive 5 years after combination surgery and chemotherapy.[51, 49]
The malignancy rate of nonfunctioning pancreatic endocrine tumors varies from 64-92% in different series.[23] One series of 25 patients with nonfunctioning neoplasms of the endocrine pancreas had 3- and 5-year survival rates of 60% and 44%, respectively, although most patients (92%) had metastatic disease.[122]
Finally, radical surgery continues to have a central role in the therapy of endocrine tumors of the pancreas. Tumor resection, the absence of liver and lymph node metastases, and the presence of MEN 1 syndrome are related to a better survival rate.[123]
Evan S Ong, MD, MS Assistant Professor of Surgery, Section of Surgical Oncology, University of Arizona College of Medicine
Evan S Ong, MD, MS is a member of the following medical societies: Society of Surgical Oncology, Americas Hepato-Pancreato-Biliary Association, American Society of Clinical Oncology
Neetu Radhakrishnan, MD Medical Oncologist, Kettering Cancer Care
Neetu Radhakrishnan, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology
Eric J Hanly, MD, Ozanan R Meireles, MD, Michael R Marohn, DO, Charles J Yeo, MD, Keith D Lillemoe, MD, and Lisa H McGrail, MD, are gratefully acknowledged for their contributions to this topic.
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That would break 8 of my mods, ss res reads spot on (2 DNA 75s, 5 DNA200 and a DNA 250) when I don't lock the res, adding 0.02 would cause all my atties to vape too hot. Having to lock the res to get it to work is a sure sign there is an issue with the connections, coil build or a mismatched material. Fair enough do that if it is the only way you can get it to work, but in general they read and refine the resistance extremely accurately and locking res is bad advice.
Yes, just adding resistance would not be great idea, but having option to do so would be welcome.
I havent had actual connection issues as coils are stable, tho 0.02 too low always, and it is not atty issue as it follows in similar fashion no matter what atty is.
This happens on single one wire coils also. So i dont think it is build related either.
Material difference could explain something?
Could this be somehow OEM lost vapes firmware related issue? / Some specific version that is affected?
Mine is a Hcigar dna 200 so its not a Lost Vapes issue quite a few people have or have had the same problem.
I also did a SS316L clapton build in a Boreas and Steam Crave Supreme and also Ijoy Tornado nano they all go funky on the DNA but on the Ijoy LUX + Joyetech + Fuchai + Istick 200 they work fine in temp mode.
I also sent the DNA back thinking is there a fault but nope no fault found.
It works great as a power only device.
Now that I fiddled with escribe more, I noticed in atomizer analyzer that it says room temperature is +10celcius more from what it actually is. Also the value seems static, no matter whether I try to cool the device or not.
Is this to be expected, or might it cause TC to fail?
@mui have you ran "Case Analyzer" on your mod? if not i suggest you run this function. this feature will calibrate your mod to read ambient/room temp better. it will never be dead on accurate but close.
be sure your battery is a quarter to half empty before running.
Someone can upload the DNA200-UD-SS_316L DJaquith V4 profile?
DNA200-UD-SS_316L DJaquith V4.csv wins for me hands down using "Coil Kings Surgical 316L Stainless Steel" wire.


During the past few months many software vendors have been releasing free licensed version softwares which in would require you to pay some license fees to the people for free.
Most of the software vendors release their older version for free so that people can usually try them out and opt in for licenses in newer version of the software. The new marketing strategy brought out by the companies definitely seems to be working in their favor.
Today's freebie though is VCOM Fix-It Utilities 7 Express which is a software that optimizes the performance of your system by providing you with options to check your PC and optimize it for optimal performance.
In order to get the VCOM Fix-It Utilities 7 Express Licensed copy worth 30$ for free, follow the steps below.


We are proud to support the lifesaving mission of Operation Smile. Through the dedication and compassion of our team across the nation, we have raised more than $500,000 to heal the smiles of children in need and help fund missions globally.
Because of your efforts, children around the world will have a brighter future and the chance to live a normal life. Thank you for your generosity, and let's make 2018 a success!


CSO came back to us to design and produce their brochure for the 2017 season. This year we had a focus on the themes and meanings behind the music, portraying them through all of the CSO collateral. We also created a mini pocket guide, which includes anecdotes and facts about orchestral music in a well designed and appealing format. The imagery we used throughout this campaign is all about the objects and images that music evokes, so we could really celebrate some of the best orchestral music on offer throughout this season.


The Wise Hippo Birth Preparation Programme Hertfordshire » Does Bishops Stortford need convincing about Hypnosis for Childbirth (Hypnobirthing)?
Does Bishops Stortford need convincing about Hypnosis for Childbirth (Hypnobirthing)?
The following has been obtained from birth outcome surveys, completed by 144 Wise Hippo clients, which is 10% of the number of clients who had birthed at the time this information was compiled.
Our vision is to empower all pregnant women, and their partners, to trust themselves and the choices they make, so they can achieve the best birth possible and know their baby had 'the right birth on the day'. We are therefore pleased to report that 100% of Wise Hippo Birthing clients, who returned their birth outcome reports, have told us that they know that their baby had the right birth on the day.
100% of respondents, some from Hertfordshire and the Bishops Stortford area, also let us know that they felt prepared and confident about their birth after they had completed their classes and that they were able to successfully use what they had learnt during their labour and birth.
72% of respondents achieved the birth that they were hoping for. What makes us unique is that our clients do not feel like they have failed, or worse traumatised, if they don't achieve that. We know there is no such thing as the 'right' way to birth, just the right birth on the day. We set realistic expectations for birth that leave our clients feeling successful.
100% of respondents have also said that they were able to make calm, informed choices. We believe this may have a bearing on the reduction in the percentage of women requiring a C-section, and of those whose labour was induced, as compared with the most recent maternity statistics for England (2013/14).
We want all women to have access to our life changing education and a key part of that is our non-judgemental approach to what is deemed to be the 'right birth'. We want to clarify therefore that The Wise Hippo Birthing Programme Bishops Stortford does not focus on a 'natural birth without drugs'. This is an important consideration as we look at the following figures. Although a low requirement for pain relieving drugs such as pethidine, diamorphine and the epidural is a by-product of our programme, some women attend our courses simply to help them let go of fear and build their confidence and not because they want to avoid for example the use of the epidural.
Finally we will look at where our Wise Hippo Birthing clients are having their babies. Ultimately women will choose to birth where they feel 'safe'. Even for those considered to be high risk who plan to birth in the hospital, or indeed those having a planned C-section, a decision has been made based on what they believe is safe for them.
18% of Wise Hippo clients birthed at home compared to the 2013 national statistics for England and Wales of 2.3%.
60% of Wise Hippo clients birthed at hospital compared to the 2013 national statistics for England and Wales of 90%.
At the time of writing comparative figures could not be obtained for Birthing Centre or Midwife Led Unit births.
The Wise Hippo Hertfordshire is based in Bishops Stortford and also covers Sawbridgeworth, Stansted, The Hadhams, The Rodings and Harlow.


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Note: This is a limited time sale that applies ONLY to the products listed above. It can not be combined with any other discount, or special combo purchase. In order to obtain the discount, the order for the products must be ALL made at one time. This special sale can not be applied to past purchases .