The functional tumors synthesize and release hormones that yield distinct clinical presentations related to the role of the hormone. The five neoplasms below are functional tumors.

Functional ICTs

Insulinomas

These are the most common of ICTs and are often benign. Insulinomas cause excessive secretion of insulin. The resultant hypoglycemia ultimately results in headaches, visual changes, confusion [13]. as well as irritability, weakness, tremors, ataxia, and seizures. Severe cases cause coma and even death.

Gastrinomas

Many of these tumors are typically either malignant or have malignant potential. They secrete elevated amounts of gastrin which cause gastric and duodenal ulcers. Collectively known as Zollinger-Ellison syndrome, the common symptoms are abdominal pain, diarrhea, steatorrhea, and gastric acid reflux. There are frequently found in the head of the pancreas although they can occur in the duodenum.

Glucagonomas

The majority of glucagonomas are malignant. They secrete excessive glucagon causing hyperglycemia and diabetes. Additionally, it leads to unintended weight loss, stomatitis, dermatitis, and anemia. Another severe complication of glucagonomas is thrombosis.

VIPomas

At the time of diagnosis, these tumors are likely to be malignant. They produce vasoactive intestinal polypeptide, which plays a role in the secretion of other hormones and causes gastrointestinal muscle relaxation. The symptoms of VIPomas include copious amounts of watery diarrhea, hypokalemia, and dehydration.

Somatostatinomas

These are large, malignant tumors that secrete somatostatin, which is a hormone that inhibits the release of others. Its sequelae include diabetes and cholelithiasis.

Non-functional ICTs

The tumors of this type are usually asymptomatic. They account for the minority of all ICTs. Almost 90% are malignant but usually diagnosed incidentally or in the later stages when their large sizes cause mechanical complication [14].

• Weight Loss

  ANSWER They might cause abdominal pain, weight loss, nausea, and vomiting. [webmd.com]

  loss for no known reason Sore tongue or sores at the corners of the mouth Too much vasoactive intestinal peptide (VIP) may cause: Very large amounts of watery diarrhea Dehydration Low potassium level in the blood Cramps or pain in the abdomen Weight [uvahealth.com]

  […] urination Feeling tired or dizzy Blood clots in the lungs VIPoma: Weight loss Abdominal cramps or pain Watery diarrhea Dehydration symptoms Symptoms related to low potassium levels. [uhhospitals.org]

  Symptoms include ulcers of the small intestine or stomach, diarrhea, stomach pain, bleeding, nausea, vomiting, weakness, fatigue, and unexplained weight loss or gain. [nyp.org]

  Symptoms may include tummy (abdominal) pain, heartburn, diarrhoea and weight loss. Gastrinomas can cause ulcers in the stomach or duodenum, which can be life-threatening if they bleed severely. [pancreaticcancer.org.uk]

• Weakness

  These include muscle weakness, aches, cramps, numbness, tingling, frequent urination, confusion, thirst, and rapid heartbeat Somatostatinoma: Diarrhea Gallstones Yellowing of the skin or eyes Unexplained weight loss High blood sugar symptoms. [uhhospitals.org]

  Possible mechanisms for explaining this apparent discrepancy include the production of immunoreactive molecules with weak or absent systemic biological activity. [ncbi.nlm.nih.gov]

  Symptoms include ulcers of the small intestine or stomach, diarrhea, stomach pain, bleeding, nausea, vomiting, weakness, fatigue, and unexplained weight loss or gain. [nyp.org]

  or dizzy Blood clots VIPoma Symptoms include: Weight loss Stomach cramps or pain Watery diarrhea Dehydration symptoms Symptoms linked to low potassium levels, such as muscle weakness, aches, cramps, numbness, tingling, frequent urination, thirst, and [cedars-sinai.org]

• Fatigue

  Symptoms of a gastrinoma Ulcers, caused by too much stomach acid Diarrhea Symptoms of an insulinoma Hypoglycemia, which causes fatigue, nervousness and shakiness, dizziness or lightheadedness, seizures, and fainting episodes Confusion Symptoms of a glucagonoma [cancer.net]

  He reported a three-month history of diffuse abdominal pain, fatigue, and blurred vision. [ncbi.nlm.nih.gov]

  Treatment-related AEs (TRAEs) occurred in 17 (68%) carcinoid and 11 (69%) pNET pts; the most frequent (≥20%) were diarrhea (n = 7, 28%) and fatigue (n = 5, 20%) in carcinoid pts and fatigue (n = 6, 38%) and diarrhea (n = 4, 25%) in pNET pts. [oncologypro.esmo.org]

  When they do, they can include: Stomach ulcers Heartburn Diabetes Weakness Fatigue Muscle cramps Indigestion Diarrhea Weight loss Skin rash Constipation Pain in your abdomen or back Yellowing of your skin or eyes Low blood sugar Diagnosis Neuroendocrine [bidmc.org]

• Anemia

  A patient with a somatostatin (SRIH)-secreting islet cell tumor, whose only symptoms were dyspepsia and anemia, is described. The diagnosis of somatostatinoma was based on high plasma SRIH concentrations and immunocytochemical findings. [ncbi.nlm.nih.gov]

  Additionally, it leads to unintended weight loss, stomatitis, dermatitis, and anemia. Another severe complication of glucagonomas is thrombosis. VIPomas At the time of diagnosis, these tumors are likely to be malignant. [symptoma.com]

  Peptic ulcer disease Anemia Gallbladder conditions (cholecystitis, cholodocholithiasis) Gastroenteritis (viral or bacterial) Hepatitis Appendicitis Gastroesophageal reflux disease Inflammatory bowel disease Pancreatitis What caused this disease to develop [cancertherapyadvisor.com]

  […] diarrhea VIPoma <10%[6] Distal pancreas (body and tail) VIP Profuse watery diarrhea Dehydration Hypokalemia Achlorhydria Somatostatinoma <5%[6] Pancreatoduodenal groove, ampullary, periampullary somatostatin Diabetes mellitus Cholelithiasis Steatorrhea Anemia [en.wikipedia.org]

• Weight Gain

  gain or loss Inflamed mouth and tongue A mass or lump in the abdomen If you are concerned about any changes you experience, please talk with your doctor. [cancer.net]

  […] loss Weight gain (unintentional) Peptic ulcer pain Vomiting blood Diarrhea Abdominal pain Note: The symptoms depend upon the type of tumor and the hormone produced. [medicine.georgetown.edu]

  Too much ACTH increases the production of steroids, which can lead to weight gain, depression, easy bruising, increased risk of infection, and darkened skin. Plus and Minus Icon There are few known risk factors for pancreatic neuroendocrine tumor. [mskcc.org]

• Diarrhea

  The flow of stomach contents back into the esophagus (gastroesophageal reflux) Diarrhea Too much insulin may cause: Low blood sugar Fast heartbeat Too much glucagon may cause: Skin rash on the face, stomach, or legs High blood sugar Blood clots Diarrhea [uvahealth.com]

  […] ulcers Pain in the belly or back Diarrhea Insulinoma: Blurred vision Weakness Fatigue (extreme tiredness) Lightheadedness Shakiness Irritability Hunger Rapid heartbeat Glucagonoma: Diarrhea Weight loss Mouth sores Skin rash or dry skin Headaches Frequent [uhhospitals.org]

  They often experience severe abdominal pain, diarrhea, and gastrointestinal bleeding with potentially life-threatening consequences. [ncbi.nlm.nih.gov]

  These may include: Medicines for stomach ulcers Therapy or over-the-counter remedies to deal with diarrhea Medicines or other strategies to keep your blood sugar in a healthy range Talk with your healthcare providers about your treatment options. [cedars-sinai.org]

• Abdominal Pain

  ANSWER They might cause abdominal pain, weight loss, nausea, and vomiting. [webmd.com]

  They often experience severe abdominal pain, diarrhea, and gastrointestinal bleeding with potentially life-threatening consequences. [ncbi.nlm.nih.gov]

  These hormones can cause low blood sugar, diarrhea, indigestion, and abdominal pain. Functional PNET types include insulinoma, gastrinoma, and glucagonoma, among others. [hopkinsmedicine.org]

  They may cause obstructive symptoms of the biliary tract or duodenum, bleeding into the gastrointestinal tract, or abdominal masses. Patients may also experience nausea, vomiting, abdominal pain, back pain, and jaundice (yellowing of the skin). [nyp.org]

• Nausea

  Symptoms include ulcers of the small intestine or stomach, diarrhea, stomach pain, bleeding, nausea, vomiting, weakness, fatigue, and unexplained weight loss or gain. [nyp.org]

  She complained of nausea, vomiting, and growing abdominal mass. Abdominal computed tomography showed multiple cysts in the whole pancreas and a calcified solid mass in the pancreatic head. [ncbi.nlm.nih.gov]

  ANSWER They might cause abdominal pain, weight loss, nausea, and vomiting. [webmd.com]

  Patients may also experience nausea, vomiting, abdominal pain, back pain, and jaundice (yellowing of the skin). More than half of these non-functioning tumors are malignant (cancerous) at the time of diagnosis. [weillcornell.org]

  In Patient 7, symptoms may progress because nausea was not the direct hormone symptom by gastrin. [academic.oup.com]

• Vomiting

  Symptoms include ulcers of the small intestine or stomach, diarrhea, stomach pain, bleeding, nausea, vomiting, weakness, fatigue, and unexplained weight loss or gain. [nyp.org]

  She complained of nausea, vomiting, and growing abdominal mass. Abdominal computed tomography showed multiple cysts in the whole pancreas and a calcified solid mass in the pancreatic head. [ncbi.nlm.nih.gov]

  ANSWER They might cause abdominal pain, weight loss, nausea, and vomiting. [webmd.com]

  Patients may also experience nausea, vomiting, abdominal pain, back pain, and jaundice (yellowing of the skin). More than half of these non-functioning tumors are malignant (cancerous) at the time of diagnosis. [weillcornell.org]

  […] bad odor Diarrhea Weight loss Too little hydrochloric acid in the stomach, which can cause digestive problems and poor absorption of vitamins and nutrients Other symptoms Abdominal pain Jaundice, which is yellowing of the skin and whites of the eyes Vomiting [cancer.net]

• Abdominal Mass

  Computed tomography (CT) scan of the chest and abdomen showed an abdominal mass that involved the small bowel, mesentery, and omentum, with lesions in the right lung and the left rib. [ncbi.nlm.nih.gov]

  They may cause obstructive symptoms of the biliary tract or duodenum, bleeding into the gastrointestinal tract, or abdominal masses. Patients may also experience nausea, vomiting, abdominal pain, back pain, and jaundice (yellowing of the skin). [weillcornell.org]

  SYMPTOMS Indigestion, increased gas, diarrhea, abdominal or back pain, abdominal mass, yellowing of the skin and the whites of the eyes, which is called “jaundice” or “icterus”. [yogavanahill.com]

• Sore Mouth

  Symptoms of glucagonomas include a distinct type of skin rash (redness, ulcers and scabbing), diabetes, depression, anaemia (low levels of red blood cells), weight loss, and a sore mouth and tongue. [pancreaticcancer.org.uk]

  mouth, altered bowel habits, venous thrombosis, and high blood glucose levels[12] VIPoma, producing excessive vasoactive intestinal peptide, which may cause profound chronic watery diarrhea and resultant dehydration, hypokalemia, and achlorhydria (WDHA [en.wikipedia.org]

• Thrombosis

  […] somatostatin Diabetes mellitus Cholelithiasis Steatorrhea Anemia Weight loss PPoma Head or pancreas pancreatic polypeptide Glucagonoma 1%[7] Body and tail of pancreas glucagon, glycentin Necrolytic migratory erythema Diabetes mellitus Diarrhea Deep vein thrombosis [en.wikipedia.org]

• Hypertension

  Patient's history of hypertension was also associated with hypertension AEs. [futuremedicine.com]

  A 22-year-old woman presented with lump in the left hypochondrium, refractory high-protein ascites and evidence of left-sided portal hypertension. [ncbi.nlm.nih.gov]

  Especially, the direct hormone symptom such as diarrhea, hypertension and hyperpigmentation may be relatively easy to improve. [academic.oup.com]

  Another risk is that India’s worst-in the-world air pollution and high rates of hypertension and diabetes have compromised young people’s health, meaning that mortality from the virus could be higher than expected. [bnnbloomberg.ca]

  The most common grade 3 or 4 adverse events in patients who received sunitinib were neutropenia (12%) and hypertension (10%). [nejm.org]

• Blurred Vision

  He reported a three-month history of diffuse abdominal pain, fatigue, and blurred vision. [ncbi.nlm.nih.gov]

  vision Weakness Fatigue (extreme tiredness) Lightheadedness Shakiness Irritability Hunger Rapid heartbeat Glucagonoma: Diarrhea Weight loss Mouth sores Skin rash or dry skin Headaches Frequent urination Feeling tired or dizzy Blood clots in the lungs [uhhospitals.org]

  The symptoms of low blood sugar are: a headache lightheadedness blurred vision weakness shaking irritability hunger Symptoms of a Glucagonoma The symptoms of a glucagonoma include: a rash on the stomach, legs, or face diarrhea unexplained weight loss [healthline.com]

  Symptoms of functional pancreatic NETs Insulinomas: Symptoms of low blood sugar including, blurred vision, headache, lightheadedness, fatigue, weakness, irritability, confusion, hunger and increased sweating. [mdanderson.org]

• Diplopia

  For example, insulinoma causes hypoglycemia, which characteristically results in CNS symptoms (e.g., diplopia, confusion, dizziness), and each of these can be caused by many other disorders. [cancertherapyadvisor.com]

• Back Pain

  Patients may also experience nausea, vomiting, abdominal pain, back pain, and jaundice (yellowing of the skin). More than half of these non-functioning tumors are malignant (cancerous) at the time of diagnosis. [weillcornell.org]

  SYMPTOMS Indigestion, increased gas, diarrhea, abdominal or back pain, abdominal mass, yellowing of the skin and the whites of the eyes, which is called “jaundice” or “icterus”. [yogavanahill.com]

  Too much gastrin may cause: Stomach ulcers that keep coming back Pain in the abdomen, which may spread to the back. [uvahealth.com]

  Symptoms of a Nonfunctional Tumor The symptoms of nonfunctional tumors include: indigestion increased gas diarrhea abdominal or back pain abdominal mass yellowing of the skin and the whites of the eyes, which is called “jaundice” or “icterus” Symptoms [healthline.com]

• Muscle Weakness

  These include muscle weakness, aches, cramps, numbness, tingling, frequent urination, confusion, thirst, and rapid heartbeat Somatostatinoma: Diarrhea Gallstones Yellowing of the skin or eyes Unexplained weight loss High blood sugar symptoms. [uhhospitals.org]

  or dizzy Blood clots VIPoma Symptoms include: Weight loss Stomach cramps or pain Watery diarrhea Dehydration symptoms Symptoms linked to low potassium levels, such as muscle weakness, aches, cramps, numbness, tingling, frequent urination, thirst, and [cedars-sinai.org]

  Low potassium level in the blood : This can cause muscle weakness, aching, or cramps, numbness and tingling, frequent urination, fast heartbeat, and feeling confused or thirsty. Cramps or pain in the abdomen. Weight loss for no known reason. [rarecancers.org.au]

• Skin Rash

  Pancreatic neuroendocrine tumors don't always cause symptoms, but when they do, they can include diarrhea, weight loss, skin rash, pain in your abdomen or back just to name a few. [youtube.com]

  When they do, they can include: Stomach ulcers Heartburn Diabetes Weakness Fatigue Muscle cramps Indigestion Diarrhea Weight loss Skin rash Constipation Pain in your abdomen or back Yellowing of your skin or eyes Low blood sugar Diagnosis Neuroendocrine [bidmc.org]

  The flow of stomach contents back into the esophagus (gastroesophageal reflux) Diarrhea Too much insulin may cause: Low blood sugar Fast heartbeat Too much glucagon may cause: Skin rash on the face, stomach, or legs High blood sugar Blood clots Diarrhea [uvahealth.com]

  […] ulcers Pain in the belly or back Diarrhea Insulinoma: Blurred vision Weakness Fatigue (extreme tiredness) Lightheadedness Shakiness Irritability Hunger Rapid heartbeat Glucagonoma: Diarrhea Weight loss Mouth sores Skin rash or dry skin Headaches Frequent [uhhospitals.org]

  When they do, signs and symptoms can include: Stomach ulcers Heartburn Diabetes Weakness Fatigue Muscle cramps Indigestion Diarrhea Weight loss Skin rash Constipation Pain in your abdomen or back Yellowing of your skin or eyes Low blood sugar Causes It's [mayoclinic.org]

• Necrolytic Migratory Erythema

  These include insulinoma presenting with hyperinsulinemic hypoglycemia; glucagonoma with necrolytic migratory erythema, diabetes mellitus, and thomboembolisms; VIPoma with watery diarrhea, hypokalemia and or hypo/achlorhydia; SSoma with diabetes mellitus [orpha.net]

  If a glucagonoma, then necrolytic migratory erythema (classic skin condition involving face, extremities and perineum that evolves as coalescing patches of erythematous papules over 7-14 days), abdominal pain, anorexia, weight loss, symptoms related to [cancertherapyadvisor.com]

  migratory erythema Diabetes mellitus Diarrhea Deep vein thrombosis Relative incidence is given as percentage of all functional pancreatic neuroendocrine tumors. [en.wikipedia.org]

• Flushing

  Somatostatinomas can cause tummy pain, gallstones, diabetes, diarrhoea, steatorrhoea (large, pale, oily poo that smells horrible and is difficult to flush down the toilet), low levels of stomach acid and weight loss. [pancreaticcancer.org.uk]

  VIPomas (excess vasoactive intestinal peptide): abdominal cramping, watery diarrhea, facial flushing. SOURCES: American Cancer Society web site, "Detailed Guide: Pancreatic Cancer." National Cancer Institute web site: "Pancreatic Cancer." [webmd.com]

  […] diarrhea Too little potassium in the blood, which can cause an irregular heartbeat, muscle cramping and weakness, and decreased reflexes Too little acid in the stomach, which can cause digestive problems and poor absorption of vitamins and nutrients Flushing [cancer.net]

  Carcinoids usually secrete serotonin, histamine and other vasoactive substances, which can occasionally cause symptoms of flushing and diarrhea (Carcinoid Syndrome). [endocrinediseases.org]

• Dermatitis

  Additionally, it leads to unintended weight loss, stomatitis, dermatitis, and anemia. Another severe complication of glucagonomas is thrombosis. VIPomas At the time of diagnosis, these tumors are likely to be malignant. [symptoma.com]

  These symptoms may include muscular weakness, lethargy, and nausea. [12] Glucagonoma Glucagonomas secrete excessive amounts of glucagon and cause a syndrome characterized by the following [43] : Dermatitis Stomatitis Weight loss Anemia The dermatitis [emedicine.medscape.com]

  The most common findings in the glucagonoma syndrome include severe dermatitis (skin rash), mild diabetes, stomatitis (mouth sores), anemia (low red blood cell count), and weight loss (96). [pathology.jhu.edu]

  (peptic ulcers, gastroesophageal reflux, diarrhea) "Gastrinoma triangle" (common bile duct, duodenum, pancreatic head) Duodenum affected more than pancreas 20 - 30% of gastrinomas are associated with MEN1 Malignant in 80% Glucagonoma: 4Ds: diabetes, dermatitis [pathologyoutlines.com]

  […] dehydration and hypokalemia Long-acting somatostatin analogues: octreotide-LAR, lanreotide-autogel Diarrhea controlled in >90% of patients Ito et al. 2013 315 ; McKenna and Edil. 2014 311 ; Burns and Edil. 2012 330 ; Ramage et al. 2012 329 Glucagonoma 60–75% Dermatitis [endocrinefacts.org]

• Hirsutism

  A 41-year-old woman presented with hirsutism, a pelvic mass, and Cushing's syndrome. Imaging studies revealed bilateral ovarian masses and a solid and cystic mass within the pancreas. [ncbi.nlm.nih.gov]

• Withdrawn

  Organizations Islet Cell Tumor Trials Acromegaly Islet Cell Tumor Pancreatic Cancer Pancreatic Diseases Pituitary Neoplasm Any 17 and under 18 - 34 35 - 50 51 - 69 70+ Available Active, not recruiting Not yet recruiting Recruiting Completed Terminated Suspended Withdrawn [patientwing.com]

  Other countries whose beneficiary status has been withdrawn include Burundi (since 2016), Mauritania (since 2019), and South Sudan (since 2014). [foreignpolicy.com]

• Confusion

  Because of its scarcity and the cytomorphologic similarity between plasma cells and endocrine cells, EMP of the pancreas may be confused with neuroendocrine (islet cell) tumors of the pancreas. [ncbi.nlm.nih.gov]

  These include muscle weakness, aches, cramps, numbness, tingling, frequent urination, confusion, thirst, and rapid heartbeat Somatostatinoma: Diarrhea Gallstones Yellowing of the skin or eyes Unexplained weight loss High blood sugar symptoms. [uhhospitals.org]

  If you are confused with the other use of the word, just say native American. [english.stackexchange.com]

  Symptoms of a gastrinoma Ulcers, caused by too much stomach acid Diarrhea Symptoms of an insulinoma Hypoglycemia, which causes fatigue, nervousness and shakiness, dizziness or lightheadedness, seizures, and fainting episodes Confusion Symptoms of a glucagonoma [cancer.net]

• Headache

  These include weakness, hunger, confusion, headaches, frequent urination, and dry skin Diagnosis If you have any of these symptoms and your healthcare provider thinks that you might have a pancreatic NET, he or she will use a host of tests to find out [uhhospitals.org]

  The symptoms of low blood sugar are: a headache lightheadedness blurred vision weakness shaking irritability hunger Symptoms of a Glucagonoma The symptoms of a glucagonoma include: a rash on the stomach, legs, or face diarrhea unexplained weight loss [healthline.com]

  Dehydration : This can cause feeling thirsty, making less urine, dry skin and mouth, headaches, dizziness, or feeling tired. [rarecancers.org.au]

  Symptoms of functional pancreatic NETs Insulinomas: Symptoms of low blood sugar including, blurred vision, headache, lightheadedness, fatigue, weakness, irritability, confusion, hunger and increased sweating. [mdanderson.org]

• Dizziness

  She reported dizziness and had recorded low capillary blood glucose despite discontinuing her diabetic medication prior to admission. [ncbi.nlm.nih.gov]

  Symptoms of a gastrinoma Ulcers, caused by too much stomach acid Diarrhea Symptoms of an insulinoma Hypoglycemia, which causes fatigue, nervousness and shakiness, dizziness or lightheadedness, seizures, and fainting episodes Confusion Symptoms of a glucagonoma [cancer.net]

  When the blood sugar gets too low patients can experience symptoms which include dizziness, confusion, abnormal behavior and even loss of consciousness. [rogelcancercenter.org]

  When this happens, the patient may feel weak or dizzy and may have chills, muscle spasms, and diarrhea as well as pain in the stomach or abdomen. Islet cell cancer is also called islet cell carcinoma. The pancreas has two basic jobs. [medicinenet.com]

  Diarrhea Insulinoma: Blurred vision Weakness Fatigue (extreme tiredness) Lightheadedness Shakiness Irritability Hunger Rapid heartbeat Glucagonoma: Diarrhea Weight loss Mouth sores Skin rash or dry skin Headaches Frequent urination Feeling tired or dizzy [uhhospitals.org]

• Irritability

  The resultant hypoglycemia ultimately results in headaches, visual changes, confusion. as well as irritability, weakness, tremors, ataxia, and seizures. Severe cases cause coma and even death. [symptoma.com]

  Diarrhea and indigestion Pain or a lump in the belly or back Nausea Loss of appetite Gastrinoma: Acid reflux Stomach ulcers Pain in the belly or back Diarrhea Insulinoma: Blurred vision Weakness Fatigue (extreme tiredness) Lightheadedness Shakiness Irritability [uhhospitals.org]

  The symptoms of low blood sugar are: a headache lightheadedness blurred vision weakness shaking irritability hunger Symptoms of a Glucagonoma The symptoms of a glucagonoma include: a rash on the stomach, legs, or face diarrhea unexplained weight loss [healthline.com]

  Symptoms may include: Feeling tired or weak Shaking or sweating Headache Hunger Nervousness, anxiety, or feeling irritable Unclear thinking or feeling uneasy Double or blurry vision Fast or pounding heartbeat If your blood sugar level gets too low, you [medlineplus.gov]

• Seizure

  An 11 year-old boy with AIDS, cerebral palsy and seizure disorder presented with intractable hypoglycemia 12 days after diagnosis of Burkitt's lymphoma. [ncbi.nlm.nih.gov]

  Symptoms of a gastrinoma Ulcers, caused by too much stomach acid Diarrhea Symptoms of an insulinoma Hypoglycemia, which causes fatigue, nervousness and shakiness, dizziness or lightheadedness, seizures, and fainting episodes Confusion Symptoms of a glucagonoma [cancer.net]

  The resultant hypoglycemia ultimately results in headaches, visual changes, confusion. as well as irritability, weakness, tremors, ataxia, and seizures. Severe cases cause coma and even death. [symptoma.com]

  Feeling tired or weak Shaking or sweating Headache Hunger Nervousness, anxiety, or feeling irritable Unclear thinking or feeling uneasy Double or blurry vision Fast or pounding heartbeat If your blood sugar level gets too low, you may faint, have a seizure [medlineplus.gov]

In addition to the evaluation of the clinical picture, the clinical assessment consists of a full personal and family history, physical examination, and appropriate testing. Laboratory studies include the measurement of the hormones, polypeptides, prostaglandins, tumor markers, and radioimmunoassays.

Laboratory tests

In the evaluation of insulinomas, investigation includes the fasting serum glucose, serum insulin level, and C-peptide suppression test.

Studies for the assessment of gastrinomas include the measurement of gastric acid secretion including the hormone's basal and maximum acid output. Furthermore, the secretion stimulation test is also useful.

Finally, a fasting serum glucagon level is used to diagnose glucagonomas.

Imaging

The primary imaging technique for localization and staging of ICTs is the CT scan with oral and intravenous contrast [15] [16]. This tool reveals the involvement of peri-pancreatic lymph node, the presence of liver metastases, as well as the blood supply. Very importantly, the CT scan guides the surgical and treatment planning.

Further testing involves angiography, which offers a closer investigation of the pancreatic arterial blood supply. This modality is used as the next step when the CT scan does not detect the tumor [17].

Another advantageous technique is the endoscopic ultrasonography, which displays the tumor and allows for a biopsy [18] [19]. One study reported that ultrasonography demonstrated more sensitivity than the combination of CT and angiography [19].

Magnetic resonance imaging (MRI) with gadolinium-enhancement is helpful as it offers key details.

Somatostatin receptor scintigraphy is beneficial. The associated radionuclide scan detects the somatostatin receptors on the primary ICTs [20]. as well as the metastatic lesions.

In a few cases where the above imaging tools cannot visualize the small tumors, selective transhepatic portal venous hormone sampling can be performed [21] [22].

• Nephrolithiasis

  The patient had MEN 1 with hyperparathyroidism and nephrolithiasis and was thought to have Zollinger-Ellison syndrome. (a) Nonenhanced CT scan shows marked gastric wall thickening. [pubs.rsna.org]

• Pancreatic Calcification

  Pancreatic calcifications in malignant islet cell tumors. Radiology. 1977;122(2):333–7. [PubMed] [Google Scholar] 15. Stark DD, Moss AA, Goldberg HI, Deveney CW. CT of pancreatic islet cell tumors. Radiology. 1984;150(2):491–4. [ncbi.nlm.nih.gov]

• Fasting Hypoglycemia

  The work-up of fasting hypoglycemia may be difficult but is crucially important because a wrong diagnosis can lead to either unnecessary pancreatectomy or a missed pancreatic tumor. [ncbi.nlm.nih.gov]

• Hypochlorhydria

  […] with hyperinsulinemic hypoglycemia; glucagonoma with necrolytic migratory erythema, diabetes mellitus, and thomboembolisms; VIPoma with watery diarrhea, hypokalemia and or hypo/achlorhydia; SSoma with diabetes mellitus, cholelithiasis, steatorrhea and hypochlorhydria [orpha.net]

  […] functional tumors Watery diarrhea with hypokalemia and achlorhydria (Verner-Morrison syndrome, pancreatic cholera) VIP may also be secreted by neurogenic neoplasms 60% 5 year survival Somatostatinoma 2-3% of pancreatic endocrine neoplasms Diabetes mellitus, hypochlorhydria [surgpathcriteria.stanford.edu]

  Glucagonoma: 4Ds: diabetes, dermatitis (necrolytic migratory erythema), deep vein thrombosis, depression Solitary, large Tail > head > 50% have metastasis at presentation VIPoma: Verner-Morrison syndrome: watery diarrhea, hypokalemia, achlorhydria / hypochlorhydria [pathologyoutlines.com]

  The clinical features of the somatostatinoma syndrome are nonspecific and include steatorrhea (oily stools), diabetes, hypochlorhydria (low blood chloride levels), and cholelithiasis (stones in the gallbladder). [pathology.jhu.edu]

• Glucagon Increased

  These release hormones that control the level of sugar in the blood – the hormone insulin decreases this level, while the hormone glucagon increases it. [cancercouncil.com.au]

  Glucagon increases glycogenolysis and gluconeogenesis and can prevent hypoglycemia. Hoff et al. have used glucagon infusions via a pump to treat NICH in a patient with meningeal sarcoma. [frontiersin.org]

• Cortisol Increased

  Cortisol increases blood pressure and blood sugar and inhibits the immune system. ACTHomas can result in Cushing’s syndrome, a disorder characterized by excessive amounts of weight gain (central obesity). [rarediseases.org]

The therapeutic approach depends on the tumor's size, location, and it metastatic status. It also reflects the overall clinical presentation and presence of co-morbidities [23]. The management of the patient involves multidisciplinary coordination between oncology, surgery, primary care, gastroenterology, endocrinology, and other relevant specialties.

Surgery

Surgical intervention is the treatment of choice. In cases with syndromic ICTs without metastasis, complete surgical resection is warranted. When the tumor is located in the pancreatic tail or body, surgical procedures include distal pancreatectomy. If the lesion is located in the pancreatic head, the Whipple procedure is the preferred procedure. Small single masses can be enucleated. If there is liver metastasis, surgical resection [24]. and debulking may be beneficial.

Ablation through radiofrequency and cryosurgery are alternative procedures for metastatic cases.

Chemotherapy

In patients with extensive metastasis, chemotherapy drugs have produced variable results [25] [26]. Examples of anti-neoplastic agents include cisplatin, 5-fluorouracil, and streptozotocin. Newer drugs are undergoing evaluation in current drug trials.

Chemoembolization

The management of liver metastasis may warrant embolization of the hepatic artery in order to obstruct blood supply to the liver tumor [27].

Hormone therapy

Octreotide, a somatostatin analogue, can be used in cases where the lesion is not resectable or when there is a residual tumor.

Other

Addressing the clinical manifestations of these tumors is paramount to prevent serious complications. For example, supportive therapy for peptic ulcers includes proton-pump inhibitor drugs and histamine blocking medications. Additionally, antidiarrheal drugs and intravenous (IV) fluids with electrolytes are other important considerations. Finally, there are medications regarding the management of blood glucose abnormalities.

Lifestyle modifications such as dietary restrictions, smoking cessation, and abstinence from alcohol are all recommended for patients with these tumors.

If the tumor is detected prior to metastasis, the outcome is typically better. The disease is likely curable if complete surgical removal is possible. For example, if the tumor is resectable, the 5-year survival rate is 55% whereas the rate is 15% when the lesion is not resectable [3]. In cases with advanced disease, aggressive treatment may prolong survival.

A significant predictor of the tumor's behavior is the tumor size which is found to be proportional to the probability of metastasis, invasion, and aggressiveness [11] [12]. Furthermore, the prognosis depends on factors such as the type of islet cell, tumor location, metastatic status, the patient's clinical profile, and if cancer has relapsed. Another pertinent prognostic factor is whether the patient has multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), or neurofibromatosis type I (NF-1).

Note that the percentage of malignant cases is lowest in insulinomas (10%) but is significantly higher in gastrinomas (60%) and glucagonomas (80%). The other types of functional ICTs are also mostly malignant as are the non-functional ones as well.

The etiology is not fully understood. The majority of islet cell tumors develop sporadically. Furthermore, it is believed that some patients have a genetic predisposition in conjunction with an environmental trigger.

ICTs comprise 3% to 5% of all pancreatic malignancies [2] [3]. The incidence of these neoplasms is about 1 per population of 100,000. Furthermore, in the United States, there are approximately 1,000 new cases annually [2].

With regards to patient demographics, ICTs have a slight predilection for women. Additionally, sporadic cases occur between the age of 30 and 60 years while the genetic forms develop in childhood or early adulthood.

Endocrine cells account for less than 5% of the pancreatic mass. These cells are distributed in clusters known as the islet of Langerhans. The three chief types of islet cells are the beta, alpha, and delta cells which secrete insulin, glucagon, and somatostatin, respectively. Furthermore, other hormones are also produced from the minor cells.

Islet cells have access to the bloodstream due to their extensive blood supply as they receive up to 15% of the pancreatic perfusion. Moreover, these cells have neural innervation from the parasympathetic and sympathetic nervous system which modulate the hormonal mechanisms of insulin and glucagon secretion.

Pathophysiology of ICTs

The pancreatic islet cells are a component of the neuroendocrine system of the pancreas and the gut. Since these cells contain high levels of amine and are capable of amine precursor uptake with decarboxylation, they are termed as APUD cells [4] [5]. These cells are pluripotent neuroendocrine cells found in the gastrointestinal tract, pulmonary mucosa, and the nervous system [6]. The APUD cells differentiate into distinct endocrine tissues [5] [7].

Since there are numerous pancreatic cell types, there are at least five different cancers. When functional, each type yields a particular metabolic and clinical picture reflecting the characteristic effects of the specific polypeptide released from the tumor cells. This is in contrast to the non-functional tumors that produces non-specific symptomatology secondary to the tumor bulk or metastases [8]. While 85% these tumors are considered functional, the remaining non-functional cases resemble the clinical picture of the exocrine adenocarcinomas [9] [10].

Histologic evaluation

ICTs display well-differential cells that are arranged in a pattern of nets, trabeculae, or ribbon. It is difficult to predict the behavior of pancreatic neoplasms based on histology. With regards to malignancy, the most remarkable histologic finding is the invasion of neighboring organs and large vasculature, and spread to lymph nodes or elsewhere. However, benign and malignant tumors may resemble each other histologically hence adding to the difficulty in differentiating between the two.

There are no preventive measures for ICTs.

Islet cell tumors (ICTs), also known as pancreatic neuroendocrine tumors, refer to the rare neuroendocrine tumors that stem from the cells of the pancreas. These well-differentiated neoplasms either develop as isolated lesions or arise from genetic syndromes [1]. There are numerous types of islet cells and each produces key hormones that play an integral role in the regulation of metabolic functions.

The main tumors are insulinomas, glucagonomas, and gastrinomas. The clinical presentation reflects the distinctive metabolic effects of these hormones. The former are all functional tumors. In contrast, there are non-functioning tumors which do not cause symptoms until late stages. The etiology of ICTs is not fully elucidated. Some are sporadic and others are likely to develop as a result of genetic and environmental interplay.

ICTs can be detected through a clinical assessment comprised of a physical exam, laboratory tests, and various imaging modalities. Laboratory tests such as measurement of hormone levels, tumor markers, and biochemical studies are key for diagnosis of the disease. Imaging techniques such as computed tomography (CT), endoscopic ultrasonography, and scintigraphy are among the diagnostic modalities that are likely to identify the presence of a lesion.

The therapeutic approach in patients with ICTs is dependent on the location and size of the mass, presence of distant metastasis, presence of co-morbidities, overall clinical picture, and other factors as well. Surgical resection is the preferred therapy, which is the only curative treatment. Furthermore, chemotherapy, hormone therapy, chemoembolization and supportive care may be used in conjunction with surgery as an adjunctive treatment or it may be used as a combination treatment strategy.

An early diagnosis and the absence of metastatic lesions is associated with a good prognosis. The presence of distant metastasis influences the outcome.

What are islet cell tumors?

These are rare tumors that develop in the pancreas. There are numerous types of pancreatic cells called the islet cells. Each type produces a certain hormone that regulates important metabolic functions. For example, the A cells make insulin, the B cells makes glucagon, and the D cells make gastrin. There are other types as well. Some of the tumors are benign while other are malignant. If they are malignant, they spread to other organs such as the liver as well as the lymph nodes.

What are the causes?

The causes are unknown. Some occur sporadically while others develop from a combination of genetic and environmental triggers. Also, these tumors may occur alone or part of genetic syndromes.

What are signs and symptoms?

Each type of tumor produces its own symptoms. In the case of insulinomas, they increase insulin levels in the body, which in turn causes low blood sugar. The following are common symptoms:

• Weakness
• Fatigue
• Headache
• Hunger
• Shaking
• Sweating
• Irritability and nervousness
• Rapid heart beat and sensations
• Fainting
• Seizure
• Coma or even death

Patients with gastrinomas produce gastrin, which is the hormone that releases acid in the stomach. Therefore, it causes stomach and duodenal ulcers. The symptoms are:

• Abdominal pain and discomfort
• Diarrhea
• Bloody vomit

Glucagonomas produce glucagon, which is the hormone that normally increases the blood sugar level. These patients experience:

• Blisters in the mouth, groin, or buttocks
• Diabetes
• Weight loss

How are these tumors diagnosed?

After assessing the patient's symptoms, the physician will obtain the personal and family history of the patient, perform a full physical examination, and order the appropriate blood tests and imaging studies.

Laboratory test include:

• Levels of specific hormones such as insulin, glucagon, or gastrin
• Tumor markers
• Radioimmunoassays

Imaging techniques include:

• Endoscopic ultrasonography with biopsy
• CT scan
• MRI
• Angiography

How are they treated?

There are numerous ways to treat these tumors. Surgical resection of the tumor may cure the disease. The therapeutic approach depends on factors such as the location of the tumor and whether it has spread. The doctor will also assess if the patient is a good surgical candidate on the basis of age and presence of other diseases.

• Surgery: the specific procedure depends on the location of the tumor and whether it has spread
• Chemotherapy: drugs are used to either kill the cancer cells or stop their growth. There are current drug trials testing out new chemotherapy medications
• Embolization: this causes blood to stop flowing to the liver
• Hormone therapy: this can block the effects of the hormone and stop the cancer's growth

Since there are complications caused by these tumors, supportive therapy is important in these patients. For example, patients with ulcers need antacid medications. Also, those with diabetes require insulin or other sugar lowering drugs.

All patients are advised to adhere to healthy diets and to quit smoking.

What is the prognosis?

The earlier the diagnosis, the better the prognosis. Surgical removal of the tumor before it spreads helps the patient achieve long-term survival.

The prognosis also depends on the type of tumor. For example, only 10% of insulinomas are malignant however 60% of gastrinomas and 80% of glucagonomas are malignant.

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