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] In 1927, Wilder et al described the first hormone-producing pancreatic tumor syndrome in a patient with hypoglycemia and a metastatic islet cell tumor, extracts of which caused hypoglycemia.[2]
Subsequent to this initial description of insulinoma syndrome, 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 types comprise a group of three tumor syndromes, termed 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:
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 nonfunctional pancreatic endocrine 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:
For discussion of other conditions with which pancreatic endocrine tumors are associated, see the following:
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]
Patients with functional pancreatic endocrine neoplasms have 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]
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 secondary to improvements in the modalities used to diagnose and treat these lesions (also see Complications and Prognosis).
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.[26, 18, 27] 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 MEN 1 syndrome.[17]
Patients with sporadic pancreatic endocrine tumors present most commonly at the age of 30-50 years.[28] In contrast, patients with pancreatic endocrine tumors that develop as part of MEN 1 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[29] :
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.[30]
First, the direct physiologic effect of hypoglycemia is neuroglycopenia, which results in the following symptoms[17] :
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.[31]
The classic triad of Zollinger-Ellison syndrome includes the following[3] :
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.[32]
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.[33, 34]
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.[35, 36]
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.[37, 38]
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.[39]
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] :
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.[42]
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[43] :
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.[44]
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.[45]
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.[46] 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.[47]
The symptoms of somatostatinoma syndrome reflect the general inhibitory action of somatostatin on global gastroenteropancreatic function, as follows:
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.
The signs and symptoms of carcinoid tumor are related to hypersecretion of serotonin (5-HT) and include the following:
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:.
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:
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.[54]
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.[55]
In patients with possible nonfunctioning pancreatic tumors, guidelines from the National Comprehensive Cancer Network (NCCN) recommend measurement of calcitonin, parathyroid hormone–related peptide (PTHrP), and growth hormone–releasing hormone (GHRH); NCCN consultants disagree over whether to measure serum pancreatic polypeptide and chromogranin A.[56] Many pancreatic endocrine tumors secrete chromogranin A, and this marker may be used for both diagnosis and follow-up.[57]
A study by Warner et al found that an ascites chromogranin A/serum chromogranin A 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.[58]
See the list below:
See the list below:
See the list below:
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.[47] 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, 61] This test in available only in select centers.
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.[56]
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.[62]
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.
View Image | Neoplasms of the endocrine pancreas. Intravenous and oral contrast-enhanced CT scan image in a patient with chronic diarrhea and elevated levels of se.... |
View Image | Neoplasms of the endocrine pancreas. CT scan with oral and intravenous contrast in a patient with a glucagon-secreting neoplasm. This 10-cm contrast-e.... |
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.[63] The images below below are from the same patient.
View Image | Neoplasms of the endocrine pancreas. CT scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm c.... |
View Image | Celiac axis angiography illustrating neoplasms of the endocrine pancreas. Contrast is seen opacifying the common hepatic artery (CHA) and splenic arte.... |
View Image | Highly selective distal angiography illustrating neoplasms of the endocrine pancreas. With the arterial catheter now advanced into the superior pancre.... |
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.[64, 65, 66] 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.[67]
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.[68] See the image below.
View Image | Neoplasms of the endocrine pancreas. Octreotide scan (anterior view) in a patient with a pancreatic endocrine tumor. The large pancreatic-tail neoplas.... |
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.[69]
Endoscopic ultrasonography
In experienced hands, transduodenal endoscopic ultrasonography (EUS) can be helpful in localizing pancreatic endocrine tumors and in assessing lymph node metastases.[70, 71]
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.
View Image | Neoplasms of the endocrine pancreas. Endoscopic ultrasonography in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body .... |
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.
View Image | Neoplasms of the endocrine pancreas. Schematic diagram of provocative angiography. Access to the central venous and arterial systems is obtained throu.... |
View Image | Neoplasms of the endocrine pancreas. Graphic depiction of the results of a selective arterial secretin stimulation test in a patient with an occult ga.... |
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.[72, 73] 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.[74]
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.[75] 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.
See the list below:
When visualized with 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 blood stream.[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:
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/mo for symptom control in patients with neuroendocrine tumors and suggested that increased 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 and thus 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 FDA in January 2018. Approval was based on the NETTER-1 clinical trial, a single-institution, single-arm, open-label trial conducted by Erasmus Medical Center in Rotterdam, Netherlands 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 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 lead to a 48% reduction in the estimated risk of death (hazard ratio 0.52, 95% 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 higher doses to be delivered to tumor whilst 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 sunitinib (37.5 mg) improved progression-free survival, overall survival, and objective response rate among 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 progression-free survival rate was 79%. Median progression-free survival 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 progression-free survival 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 thromboembolic events.[93]
Treatments for specific syndromes may include the following:
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).[56]
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:
See the list below:
Patients with unresectable insulinoma may gain some symptomatic relief by eating frequent small meals with a high starch and complex carbohydrate content.[30] 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.
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, particulalry when tumors are small and indolent. Additional recommendation include the following[56] :
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.
Clinical Context: 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.
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.
Clinical Context: 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.
Radiolabeled somatostatin analog binds to somatostatin receptor-expressing cells.
Clinical Context: 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.
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.
Clinical Context: 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.
Clinical Context: Inhibits topoisomerase II and produces free radicals that may destroy DNA. Combination of these events can inhibit growth of neoplastic cells.
Clinical Context: Fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase and interferes with RNA synthesis and function. Has some effect on DNA.
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]
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.
See the list below:
See the list below:
See the list below:
Late in the course of pancreatic endocrine tumors, patients can have morbidity related to the mass effects of the disease.
Morbidity resulting from the effects of excess hormonal production by functional neoplasms of the endocrine pancreas occurs sooner than the mass effects in the course of the disease.
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] :
Permanent diabetes mellitus can mandate extended pancreatic tumor resection.
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, 28]
Neoplasms of the endocrine pancreas have patterns of initial tumor spread that are similar to those of other gastrointestinal carcinomas, as follows:
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.[114]
Patients with gastrinomas have a poorer prognosis; 60% of these tumors are malignant.[115] 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:
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.[46, 45, 120] 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.[121, 122]
Most somatostatinomas (84%) are metastatic at the time of presentation, but a number of patients survive 5 years after combination surgery and chemotherapy.[50, 48]
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.[123]
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.[124]
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. 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. 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. 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).