Neuroendocrine tumors (NETs) are slow-growing neoplasms capable of storing and secreting different peptides and neuroamines. Some of these substances cause specific symptom complexes, whereas others are silent. They usually have episodic expression, and the diagnosis is often made at a late stage. Although considered rare, the incidence of NETs is increasing. For these reasons, a high index of suspicion is needed. In this article, the different clinical syndromes and the pathophysiology of each tumor as well as the new and emerging biochemical markers and imaging techniques that should be used to facilitate an early diagnosis, follow-up, and prognosis are reviewed.
Key points
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Neuroendocrine gastroenteropancreatic tumors are a heterogeneous group of tumors that arise from the diffuse endocrine system.
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They derive from the embryologic endocrine system predominantly in the gut in the gastric mucosa, the small and large intestine, and the rectum but are also found in the pancreas, lung, ovaries, C cells of thyroid, and autonomic nervous system.
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They are slow-growing and capable of storing and secreting different peptides and neuroamines.
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Some of these substances cause specific clinical syndromes, whereas others do not.
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Biomarkers can be used for diagnosis, following the patient’s prognosis.
Introduction
Neuroendocrine tumors (NETs) are tumors that arise from the diffuse endocrine system. They are slow-growing and capable of storing and secreting different peptides and neuroamines. Some of these substances cause specific clinical syndromes; others do not.
Although considered rare, the annual incidence of NETs has risen to 40 to 50 cases per million due to the availability of improved techniques for tumor detection. A review of the Surveillance, Epidemiology, and End Results (SEER) database showed a 5-fold increase in the incidence of NETs from 1.09 per 100,000 in 1973 to 5.25 per 100,000 in 2004. In the United States, the prevalence is estimated to be 103,312 cases, which is twice the prevalence of gastric and pancreatic cancers combined.
There are impediments to the diagnosis of NETs. They are not first in the differential because they comprise less than 2% of the gastrointestinal (GI) malignancies. Symptoms are often nonspecific, and the manifestations mimic a variety of disorders. A delay in diagnosis can also occur when the biopsy material is not examined for secretory peptides. Tumors may then be labeled erroneously as adenocarcinoma, affecting the management and underestimating prospects for survival. There is typically a delay of many years before the right diagnosis is made, by which time metastases have occurred and survival has directly been affected, as shown in Fig. 1 . Learning to recognize the symptoms is very important for early diagnosis. Clinically suspicious symptoms necessitate biochemical testing.
The biochemical markers are hormones or amines secreted by the neuroendocrine cells. Some are secreted by most NETs; others are specific to a type of tumor and lead to the diagnosis. NETs can also be nonfunctional and present with signs and symptoms due to the mechanical complications (pain, obstruction, bleeding), but those silent tumors can at any point in time start producing hormones and become syndromic. The substance secreted by one tumor may change with time and yield an entirely different clinical syndrome. Indeed, metastases are known to each secrete different hormones than the parent tumor. NETs can also secrete other substances not related to their original cell properties, like cytokines, autoantibodies, and so on, which result in paraneoplastic syndromes.
In general, NETs are named according to the hormone they produce (eg, gastrinoma if gastrin secreting, vasoactive intestinal polypeptide [VIP]-oma if VIP secreting).
The authors suggest an approach to diagnosing an NET based on the clinical presentation and the biochemical markers, as summarized in Table 1 .
| Clinical Presentation | Syndrome | Tumor Type | Sites | Hormones |
|---|---|---|---|---|
| Flushing | Carcinoid Medullary carcinoma of thyroid PHEO | Carcinoid C-cell tumor Tumor of chromaffin cells | Mid/foregut Gastric Thyroid C cells Adrenal and sympathetic nervous system | Serotonin, CGRP, calcitonin Metanephrine and Normetanephrine |
| Diarrhea, abdominal pain, and dyspepsia | Carcinoid, WDHHA, ZE, PP, MCT | Carcinoid, VIPoma, Gastrinoma, PPoma, medullary carcinoma thyroid thyroid, mastocytoma | As above, pancreas, mast cells, thyroid | As above, VIP, gastrin, PP, calcitonin |
| Diarrhea/steatorrhea | Somatostatin Bleeding GI tract | Somatostatinoma, neurofibromatosis | Pancreas Duodenum | Somatostatin |
| Wheezing | Carcinoid | Carcinoid | Gut/pancreas/lung | SP, CGRP, serotonin |
| Ulcer/dyspepsia | Zollinger Ellison | Gastrinoma | Pancreas/duodenum | Gastrin |
| Hypoglycemia | Whipple’s triad | Insulinoma, sarcoma, hepatoma | Pancreas, retroperitoneal liver | Insulin, IGF1, IGF11 |
| Dermatitis | Sweet syndrome | Glucagonoma | Pancreas | Glucagon |
| Pellagra | Carcinoid | Midgut | Serotonin | |
| Dementia | Sweet syndrome | Glucagonoma | Pancreas | Glucagon |
| Diabetes | Glucagonoma | Glucagonoma | Pancreas | Glucagon |
| Somatostatin | Somatostatinoma | Pancreas | Somatostatin | |
| DVT, steatorrhea, cholelithiasis Neurofibromatosis | Somatostatin | Somatostatinoma | Pancreas Duodenum | Somatostatin |
| Silent, liver metastases | Silent | PPoma | Pancreas | PP |
| Fever | With weight loss cachexia | Any | Any | Cytokines (IL-6, NF-κβ, TNF-α) |
| Bone metastasis | Pain/fracture/spinal compression | Any | Any | Bone Alk phos N-telopeptide |
| Paraneoplastic syndromes | Peripheral neuropathy, myopathy, mysthenia, CIDP, Lambert Eaton, cerebellar ataxia | Any | Any | Antibodies to calcium channels, acetylocholine receptors, C-ANCA, P-ANCA, Hu |
NETs are classified based on the embryologic origins and the vascular supply of the digestive tract into foregut (lung, stomach, liver, biliary tract, pancreas, the first portion of the duodenum, and the ovaries), midgut (the distal duodenum, small intestines, appendix, right colon, and the proximal transverse colon), and hindgut (the distal transverse colon, left colon, and the rectum) tumors.
Introduction
Neuroendocrine tumors (NETs) are tumors that arise from the diffuse endocrine system. They are slow-growing and capable of storing and secreting different peptides and neuroamines. Some of these substances cause specific clinical syndromes; others do not.
Although considered rare, the annual incidence of NETs has risen to 40 to 50 cases per million due to the availability of improved techniques for tumor detection. A review of the Surveillance, Epidemiology, and End Results (SEER) database showed a 5-fold increase in the incidence of NETs from 1.09 per 100,000 in 1973 to 5.25 per 100,000 in 2004. In the United States, the prevalence is estimated to be 103,312 cases, which is twice the prevalence of gastric and pancreatic cancers combined.
There are impediments to the diagnosis of NETs. They are not first in the differential because they comprise less than 2% of the gastrointestinal (GI) malignancies. Symptoms are often nonspecific, and the manifestations mimic a variety of disorders. A delay in diagnosis can also occur when the biopsy material is not examined for secretory peptides. Tumors may then be labeled erroneously as adenocarcinoma, affecting the management and underestimating prospects for survival. There is typically a delay of many years before the right diagnosis is made, by which time metastases have occurred and survival has directly been affected, as shown in Fig. 1 . Learning to recognize the symptoms is very important for early diagnosis. Clinically suspicious symptoms necessitate biochemical testing.
The biochemical markers are hormones or amines secreted by the neuroendocrine cells. Some are secreted by most NETs; others are specific to a type of tumor and lead to the diagnosis. NETs can also be nonfunctional and present with signs and symptoms due to the mechanical complications (pain, obstruction, bleeding), but those silent tumors can at any point in time start producing hormones and become syndromic. The substance secreted by one tumor may change with time and yield an entirely different clinical syndrome. Indeed, metastases are known to each secrete different hormones than the parent tumor. NETs can also secrete other substances not related to their original cell properties, like cytokines, autoantibodies, and so on, which result in paraneoplastic syndromes.
In general, NETs are named according to the hormone they produce (eg, gastrinoma if gastrin secreting, vasoactive intestinal polypeptide [VIP]-oma if VIP secreting).
The authors suggest an approach to diagnosing an NET based on the clinical presentation and the biochemical markers, as summarized in Table 1 .
| Clinical Presentation | Syndrome | Tumor Type | Sites | Hormones |
|---|---|---|---|---|
| Flushing | Carcinoid Medullary carcinoma of thyroid PHEO | Carcinoid C-cell tumor Tumor of chromaffin cells | Mid/foregut Gastric Thyroid C cells Adrenal and sympathetic nervous system | Serotonin, CGRP, calcitonin Metanephrine and Normetanephrine |
| Diarrhea, abdominal pain, and dyspepsia | Carcinoid, WDHHA, ZE, PP, MCT | Carcinoid, VIPoma, Gastrinoma, PPoma, medullary carcinoma thyroid thyroid, mastocytoma | As above, pancreas, mast cells, thyroid | As above, VIP, gastrin, PP, calcitonin |
| Diarrhea/steatorrhea | Somatostatin Bleeding GI tract | Somatostatinoma, neurofibromatosis | Pancreas Duodenum | Somatostatin |
| Wheezing | Carcinoid | Carcinoid | Gut/pancreas/lung | SP, CGRP, serotonin |
| Ulcer/dyspepsia | Zollinger Ellison | Gastrinoma | Pancreas/duodenum | Gastrin |
| Hypoglycemia | Whipple’s triad | Insulinoma, sarcoma, hepatoma | Pancreas, retroperitoneal liver | Insulin, IGF1, IGF11 |
| Dermatitis | Sweet syndrome | Glucagonoma | Pancreas | Glucagon |
| Pellagra | Carcinoid | Midgut | Serotonin | |
| Dementia | Sweet syndrome | Glucagonoma | Pancreas | Glucagon |
| Diabetes | Glucagonoma | Glucagonoma | Pancreas | Glucagon |
| Somatostatin | Somatostatinoma | Pancreas | Somatostatin | |
| DVT, steatorrhea, cholelithiasis Neurofibromatosis | Somatostatin | Somatostatinoma | Pancreas Duodenum | Somatostatin |
| Silent, liver metastases | Silent | PPoma | Pancreas | PP |
| Fever | With weight loss cachexia | Any | Any | Cytokines (IL-6, NF-κβ, TNF-α) |
| Bone metastasis | Pain/fracture/spinal compression | Any | Any | Bone Alk phos N-telopeptide |
| Paraneoplastic syndromes | Peripheral neuropathy, myopathy, mysthenia, CIDP, Lambert Eaton, cerebellar ataxia | Any | Any | Antibodies to calcium channels, acetylocholine receptors, C-ANCA, P-ANCA, Hu |
NETs are classified based on the embryologic origins and the vascular supply of the digestive tract into foregut (lung, stomach, liver, biliary tract, pancreas, the first portion of the duodenum, and the ovaries), midgut (the distal duodenum, small intestines, appendix, right colon, and the proximal transverse colon), and hindgut (the distal transverse colon, left colon, and the rectum) tumors.
Clinical presentation
The Classic Carcinoid Syndrome
Classic carcinoid syndrome is the result of hypersecretion of vasoactive amines (eg, serotonin, histamine, tachykinins, and prostaglandins). It is common with small intestine NETs but also occurs with bronchial, ovarian, and other foregut carcinoids. Because the liver can inactivate these substances, carcinoid syndrome typically presents after hepatic metastasis has occurred. However, this is not essential in foregut NETs.
The clinical manifestations are flushing (which occurs in 84% of patients), diarrhea (70%), and heart disease (37%), but symptoms could also be widespread to include bronchospasm (17%) and myopathy (7%). Other recently recognized associated symptoms include abnormal increase in skin pigmentation, which is a pellagra-like eruption (5%), arthropathy, paraneoplastic neuropathy, and edema. Mesenteric fibrosis is associated with midgut carcinoids even in the absence of a visible mass and could compress the vessels, which leads to bowel ischemia and malabsorption.
The specific etiologic substances of each of the manifestations are not known. Serotonin, prostaglandin, 5-hydroxytryptophan (5-HTP), substance P (SP), kallikrein, histamine, dopamine, and neuropeptide K are thought to be involved. Pancreatic polypeptide (PP) and motilin levels are often elevated.
Flushing
Although flushing is a cardinal manifestation of carcinoid syndrome, it occurs in other conditions like menopause, panic attacks, medullary thyroid cancer, autonomic neuropathy, mastocytosis, and simultaneous ingestion of chlorpropamide and alcohol. Table 2 lists tests suggested to help with the differential.
| Clinical Condition | Tests |
|---|---|
| Carcinoid | 5-HIAA, 5-HTP, SP, CGRP, CgA |
| Medullary carcinoma of the thyroid | Calcitonin, RET proto-oncogene |
| PHEO/paraganglioma | Plasma fractionated metanephrines and catecholamines |
| Autonomic neuropathy | Heart rate variability, 2H postprandial glucose |
| Menopause | Follicle stimulating hormone |
| Epilepsy | Electroencephalogram |
| Panic | Pentagastrin/ACTH |
| Mastocytosis | Plasma histamine, urine tryptase |
| Hypomastia, mitral valve prolapse | Cardiac echo |
When the flushing is dry, it is due to a carcinoid tumor until proven otherwise.
The flush in foregut tumors tends to be of protracted duration, is often a purplish or violaceous hue, and frequently results in telangiectasia and hypertrophy of the skin of the face and upper neck. The face may assume a “leonine” characteristic, resembling that seen in leprosy or acromegaly.
The flush in midgut tumors is of a faint pink to red color and involves the face and upper trunk down to the nipple line. It is initially provoked by alcohol and tyramine-containing food, like blue cheese, chocolate, red wine, and red sausage. With time, it becomes spontaneous. It usually lasts for a few minutes and occurs many times a day. It generally does not lead to permanent discoloration of the skin.
It is ascribed to several neurohumor: prostaglandins, kinins, serotonin, dopamine, histamine, 5-hydroxyindole acetic acid (5-HIAA), kallikrein, SP, neurotensin, motilin, somatostatin release inhibitory factor, VIP, neuropeptide K, and gastrin-releasing peptide (GRP). Feldman and O’Dorisio have reported a further increase in SP and neurotensin levels during ethanol-induced facial flushing. These neuropeptide abnormalities also frequently occur in patients with other forms of flushing and may be pathogenic.
Pentagastrin provocation has improved reliability compared with the calcium infusion stimulation test. It has occasional false negative results in patients with subclinical disease. In the authors’ experience, pentagastrin uniformly induced flushing in 11 patients with gastric NET (GNET), and serum SP levels increased in 80%.
Diarrhea
Diarrhea is secretory in nature like all endocrine diarrheas. As opposed to osmotic diarrhea, it generates a large amount of stool with no osmotic gap, and the key is that it persists with fasting. It occurs in other syndromes like watery diarrhea hypokalemia, hypochlorhydria, acidosis (WDHHA syndrome), Verner-Morrison syndrome (VIPoma), Zollinger-Ellison syndrome (ZES; gastrinoma), calcitonin-secreting tumors (medullary carcinoma of the thyroid or C-cell hyperplasia), PNET-secreting pancreatic polypeptide (PPoma), and SP-secreting tumors.
In the gastrinoma syndrome, the diarrhea is associated with steatorrhea, and it improves with administration of a proton pump inhibitor (PPI) or histamine 2 (H2) blockers. The acidity in the duodenum and small intestine inactivates lipase, amylase, and trypsin, damages the mucosa of the small intestine, and precipitates the succus entericus, thereby causing malabsorption and steatorrhea.
In VIPoma, the diarrhea is associated with hypercalcemia. VIP stimulates GI secretions and increases the rate of fluid delivery from the proximal to the distal small bowel so it exceeds its absorptive capacity. The diarrhea is watery, and there is great loss of bicarbonate and potassium.
C-cell hyperplasia syndrome is a more recently described cause of secretory diarrhea and flushing. Total thyroidectomy is the treatment of choice.
The different mechanisms involved in the generation of the diarrhea are illustrated in Fig. 2 .
Carcinoid Heart Disease
Carcinoid heart disease is characterized by fibrous endocardial thickening that mainly involves the right side of the heart. This fibrous tissue characteristically devoid of elastic fibers is known as carcinoid plaque. It causes retraction and fixation of the tricuspid and pulmonary valves, which leads to valvular regurgitation, but pulmonary and tricuspid stenosis may also occur. The cause is unclear but direct actions of serotonin and bradykinin have been implicated in animal studies. The clinical presentation is that of right-sided heart failure with fatigue, dyspnea, ascites, edema, and cardiac cachexia. Left-heart disease is uncommon.
Bronchoconstriction
Bronchoconstriction is clinically apparent as wheezing. The differential diagnosis includes asthma and chronic obstructive pulmonary disease. The bronchospasm is usually caused by SP, histamine, or serotonin.
Pellagra
Pellagra occurs when niacin becomes deficient as its precursor tryptophan is shunted toward serotonin production.
Blood and urine biomarkers potentially useful for diagnosis and follow-up
Several circulating tumor markers have been evaluated for the diagnosis and follow-up of NETs; however, a tissue confirmation is needed to make the diagnosis. Measurement of specific hormones may be helpful and is used in conjunction with imaging to follow clinical status and treatment response. There is controversy over the need for biomarkers and the frequency with which they should be sampled in following progress and response to intervention. In some instances, the relationship between the clinical syndrome and the hormone implicated is clear, in which case the specific hormone causing the clinical syndrome should be measured and followed over time, for example, gastrin in gastrinoma syndrome. Other markers may also be secreted by less well-differentiated tumors and nonfunctioning ones. The key is to identify few biomarkers in a particular patient and follow them over time in conjunction with symptoms and measurements of tumor bulk.
Potential Diagnostic Markers
Potential diagnostic markers include chromogranin A (CgA), chromogranin B (CgB), chromogranin C, 5-HIAA, pancreastatin, and PP.
Markers Useful in Follow-Up
Markers that may be useful in follow-up include pancreastatin, which helps monitor response to surgery and predict tumor growth. Neurokinin A is a prognosticating marker when followed during treatment. Neuron-specific enolase (NSE) has a very low false negative rate, which makes it a good marker for follow-up.
Chromogranin A
CgA is a most important marker. It is a 49-kDa acidic polypeptide present in the secretory granules of all neuroendocrine cells. Its sensitivity varies between 53% and 68%, and the specificity varies between 84% and 98%. A recent meta-analysis of 13 studies has shown a high sensitivity of 73% and specificity of 95% for the diagnosis of NETs. CgA level should be measured while fasting, and exercise should be avoided before the testing because both eating and exercise lead to increased levels. Somatostatin analogues affect the CgA level so the serial measurements should be done at the same interval from the injections.
There are caveats to the use of CgA as a universal tumor marker for NETs. First, the level of CgA correlates with tumor volume ; hence, small tumors may be associated with a normal level. Second, false positive measurements are reported in common conditions, including decreased renal function, liver or heart failure, chronic gastritis, inflammatory bowel disease, hyperthyroidism, PPI use, and even benign essential hypertension and exercise-induced physical stress. Also, elevations of CgA are reported in malignant non-NETs like breast cancer and hepatocellular carcinoma. These problems are not seen with CgB or pancreastatin.
The “pearls” and pitfalls” on the use of CgA are shown in Box 1 .
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Try and stay with the same laboratory
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Very different levels, for example, less than 30 ng/mL to less than 5 pmol/L
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Is very helpful when you know you have an NET
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May be elevated when there is no actual NET
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Severe hypertension
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Gastric acid suppression (PPIs)
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Renal insufficiency
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May be a good marker of response to therapy
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Does not correlate with symptoms
CgA also has a prognostic role in well-differentiated tumors. In midgut NETs, an increase in CgA level greater than 5000 μg/L is an independent predictor of shorter survival of 33 months compared with 57 months. A reduction of the level by more than 80% after surgery predicts symptom relief and better outcome even after incomplete cytoreduction.
Urinary 5-Hydroxyindole Acetic Acid (24-hour Collection) as a Biomarker for Neuroendocrine Tumors
5-HIAA, a serotonin degradation product, is a useful laboratory marker for serotonin-secreting NETs. It is more useful than the serum serotonin level because the latter varies during the day depending on the level of activity and stress. This test has 88% specificity. It is used for diagnosis and follow-up. The reference range varies between laboratories, but is approximately 2 to 8 mg per day.
Certain foods and medications should be avoided during the collection because they increase the level of urinary 5-HIAA: bananas, kiwis, pineapple, plantains, plums, and tomatoes. Also, moderate elevations are seen with ingestion of avocado, black olives, spinach, broccoli, cauliflower, eggplant, cantaloupe, dates, figs, grapefruit, and honeydew melon. Drugs that can increase 5-HIAA include acetanalid, phenacetin, reserpine, glyceryl guiacolate (found in cough syrups), and methocarbamol. Drugs that decrease the level are chlorpromazine, heparin, imipramine, isoniazid, levodopa, monoamine oxidase inhibitors, methenamine, methyldopa, phenothiazines, promethazine, and tricyclic antidepressants.
It is presumed that foregut carcinoids are deficient in dopa-decarboxylase, so they poorly convert 5-HTP to 5-hydroxytryptamine (serotonin), which explains the only modest increase in 5-HIAA in those patients.
Plasma 5-Hydroxyindole Acetic Acid as a Biomarker for Neuroendocrine Tumors
Measuring a single fasting plasma 5-HIAA level is much more convenient than the 24-hour urine collection. A recent study compared the 2 assays in a group of 115 individuals with all types of NETs (among which 72 had midgut tumors) and 47 patients with midgut tumors metastatic to the liver. They found a statistically significant correlation between the urine and plasma assays, indicating that these are equivalent. A prospective study is needed to determine its sensitivity and specificity to detect primary tumors, recurrence, or progression of the disease over time.
Overall, CgA seems a better tumor marker than 5-HIAA despite its limitations. Fig. 3 shows the percent positivity of CgA versus 5-HIAA.
Pancreastatin as a Biomarker for Neuroendocrine Tumors
Pancreastatin is a posttranslational processing product of CgA. It has been proposed as an alternative biomarker to CgA, because the level is less susceptible to nonspecific effects and the assay is more standardized. When elevated at diagnosis, it has a negative prognostic value. It correlates with the number of liver metastases, so it is also useful for follow-up. It has been shown to be a better predictor of tumor growth than CgA. Increasing levels during somatostatin analogue therapy is associated with poor survival. An increase in level even if the tumor seems to respond to tyrosine kinase inhibitors predicts mortality. A level higher than 5000 pg/mL is associated with periprocedure mortality in patients who underwent hepatic artery chemoembolization. Pancreastatin may also monitor response to surgery, and less than 30% debulking is associated with an increase in levels. Higher levels are associated with worse progression-free and overall survival in midgut and pancreatic NETs independent of age, site, and presence of metastases. It also may identify surgical patients at high risk of recurrence. These observations suggest that pancreastatin is potentially a very useful marker not only for diagnosis but also, more importantly, for monitoring treatment response.
Neurokinin A as a Biomarker for Neuroendocrine Tumors
Neurokinin A (NKA) is a tachykinin that has a highly sensitive and specific radioimmunoassay. It may be an important marker for prognosis. When NKA levels continue to increase despite treatment with somatostatin analogues, patients have poorer prognosis: 1-year survival decreases from 87% to 40%.
Neuron-specific Enolase as a Biomarker for Neuroendocrine Tumors
NSE is a dimer of the glycolytic enzyme enolase. It is mainly present in the cytoplasm of cells of neuronal and neuroectodermal origin. NSE is elevated in only 30% to 50% of patients with NETs, especially the poorly differentiated ones. It is a 100% sensitive but has a very low specificity of 32.9%, which makes it a useful marker for follow-up of patients with a known diagnosis of NET but is not very useful as a diagnostic tool.
Other secreted molecules can be measured: CgB and chromogranin C, neuropeptide K, PP, and SP, but there are insufficient data to evaluate their usefulness as biomarkers in NETs.
Pancreatic neuroendocrine tumors
Classification
Pancreatic neuroendocrine tumors (PNETs) are divided into 2 groups: those associated with a functional syndrome due to the secretion of a biologically active substance and those that are nonfunctional (NF-PNETs). Approximately 10% to 30% of PNETs are functional. PNETs represent 1.3% of all pancreatic neoplasms. However, the number of patients diagnosed with PNETs has been increasing. An epidemiologic survey in Japan showed a 1.7 times higher incidence of NF-PNETs in 2010 compared with 2005.
With all pancreatic NETs, one should always screen for multiple endocrine neoplasia type I (MEN-1) syndrome by measuring ionized calcium, serum parathyroid hormone (PTH), and prolactin.
NF-PNETs have an annual incidence of 1.8 in female patients and 2.6 in male patients per million, according to the SEER. They usually become clinically apparent when they reach a size that causes compression. In the past, 70% were more than 5 cm in size. However, the mean tumor diameter decreased in the last decades, mainly because of the widespread use of cross-sectional imaging technique. They are malignant in 60% to 90% of cases, and 60% to 85% have metastasized to the liver at the time of diagnosis. Although they do not secrete a hormone responsible for a syndrome, they do release substances that aid in their diagnosis: CgA (70%–100%) and PP (50%–100%). NF-PNETs have a 5-year survival rate of 43%.
Functional PNETs include insulinomas, which are the most common, followed in order of frequency by gastrinomas, glucagonomas, VIPomas, and somatostatinomas. Other rare functioning PNETs include those secreting adrenocorticotropic hormone (ACTH; ACTHomas), growth-hormone releasing factor (GRFomas), PTH-related peptide (PTHrp-omas), and those causing the carcinoid syndrome. Very rarely, PNETs secrete luteinizing hormone, renin, insulin-like growth factor (IGF)-II, glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), ghrelin, calcitonin-related peptide, or erythropoietin.
Clinical Presentation of Pancreatic Neuroendocrine Tumors
PNETs can have quite different clinical presentations, secretory products, and histochemistry ( Table 3 ).
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Systemic Therapies for Advanced Pancreatic Neuroendocrine Tumors
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