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Islet Cell Tumors Or Neuroendocrine Tumors

  • Pancreatic Neuroendocrine Tumors May Be Part Of;
    - Von Hippel-Lindau disease
    - Neurofibromatosis-1
    - Tuberous sclerosis
    - MEA type I syndrome
  • Pancreatic Neuroendocrine Tumors : CT Findings
    - Hypervascular primary mass
    - Hypervascular liver metastases and nodes
    - Pancreatic duct obstruction rare (except in serotonin producing tumors)
    - Often greater than 5 cm
    - IV tumor thrombus not uncommon
  • “Serotonin produced by pancreatic neuroendocrine tumors can induce fibrosis and pancreatic duct obstruction. Pancreatic neuroendocrine tumors should be considered when CT shows a small hypervascular mass associated with upstream pancreatic duct dilatation or atrophy. Evidence of small pancreatic neuroendocrine tumors should be sought in cases of idiopathic pancreatic duct stenosis.”
    Small serotonin-producing neuroendocrine tumor of the pancreas associated with pancreatic duct obstruction
    Kawamoto S, Shi C, Hruban RH, Choiti MA, Schulick RD, Fishman EK, Siegelman SS
    AJR 2011 Sep 197(3); W482-8
  • Treatment and Prognosis of PETs
    - Surgery is the only curative therapy
    - Octreotide for patients with liver metatases
    - RF ablation or resection of liver metastases
    - Chemoembolization of liver metastases
    - New chemotherapeutic options
  • Treatment and Prognosis of PETs

    3 year survival is over 80% without metastases and 56% with hepatic metastases

    Poor prognostic factors include;
    - Size over 4 cm
    - Vascular or neural invasion
    - High mitotic rate
    - Hi Ki-67 index
    - Necrosis
    - Chromosomal losses or gains
    - Syndromes Associated with PETs

    VHL syndrome 
    - Retinal and CNS hemangioblastomas
    - Clear cell renal cell carcinomas
    - Pheochromocytomas
    - Pancreatic serous cystadenoma (17-56%)
    - PET (12-17%) 
  • Syndromes Associated with PETs

    Multiple endocrine neoplasia type 1 (MEN1)
    - Parathyroid hyperplasia or adenomas (>90%)
    - Endocrine tumors of pancreas or duodenum (30-80%)
    - Pituitary adenomas (20-65%) 
  • Nonfunctioning PETs: Facts
    - Average size is 5-6 cm but recently we are detecting ever smaller lesions
    - Lesions may have areas of necrosis and of calcification
    - They are evenly distributed throughout the gland
    - Metastatic disease is present at presentation in 60-80% of cases
  • Nonfunctioning PETs: Facts
    - Although they are considered nonfunctioning they may secrete pancreatic polypeptide or other hormones but without clinical symptoms as the hormone secreted may be inert or too low an about to cause symptoms
    - Mean age is around 55 years with a slight female predominance
    - Most cases are sporadic but is the typical PET in patients with MEN1 and VHL syndromes
  • Somatostatinoma: Facts
    - 80 % of cases are incidental findings while 20% have symptoms ranging from diabetes mellitus, steatorrhea, diarrhea, cholelithiasis, to weight loss.
    - Somatostatin inhibits intestinal absorption and release of insulin, glucagon,gastrin and pancreatic enzymes which lead to the symptoms discussed above
    - About half of Somatostatinoma arise in the pancreas, most commonly in the pancreatic head
    - Average size is 5-6 cm and metastases occur in 50-75% of patients
  • Somatostatinoma: Facts
    - Less than 2% of PETs
    - Average age at presentation is 50 years
    - Male to female ratio is 1:1
    - Most occur in the pancreas or periampullary region of the duodenum
    - Duodenal Somatostatinomas are associated with neurofibromatosis I
  • Vipoma: CT Findings
    - Most common in the tail of the pancreas
    - Mean size at diagnosis is 5 cm
    - Small lesions enhance homogeneously while larger lesions are cystic and may contain calcification
    - Most are malignant with metastases present at presentation in 60-80% of cases
  • Vipoma: facts
    - Secretion of VIP leads to profuse watery diarrhea and hypokalemia

    - Usually occurs in 5th-6th decade of life
    - Referred to as Verner-Morrison syndrome, pancreatic choleram and WHDA syndrome (watery diarrhea, hypokalemia, achlorhydria)
    - Around 75% of Vipomas arise in the pancreas, 20% were extrapancreatic and neurogenic, and the remainder were extrapancreatic and nonneurogenic
  • Glucagonoma : CT Findings
    - Vascular mass
    - Tumor usually 5-6 cm
    - Lesions over 5 cm oftem have metastatic disease especially to liver
  • Glucagonoma syndrome is the 4D syndrome
    - Dermatitis
    - Diabetes
    - Deep vein thrombosis
    - Depression
  • Glucagonoma: Facts
    - Average age is 40-60 years
    - Male and female ratio is 1:1
    - Most Glucagonomas are sporadic and rarely associated with MEN1
    - Most are malignant and about 75% ultimately fatal
    - Most arise in body or tail of the pancreas
    - Glucagonoma syndrome is the 4D syndrome
  • Gastrinoma: CT findings
    - Often arise in gastrinoma triangle, an area bounded by the junctions of the cystic duct and CBD superiorly, the second and third protions of the duodenum inferiorly, and the neck and body of the pancreas medially
    - Up to 80% of gastrinomas originate from the duodenum
    - Average size is 3-4 cm when in pancreas and 1 cm when in duodenum
    - Tumors are typically vascular, homogeneous or have ringlike enhancement
  • Gastrinoma: facts
    - Most are sporadic but most common functioning PET in patients with MEN1 with up to 25% of all gastrinomas in these patients
    - 60% of gastrinomas develop malignant behavior
    - Elevated gastrin levels lead to peptic ulcer disease which is severe and often post bulbar in location
    - Serum gastrin levels usually over 1000 pg/ml with normal < 100 pg/ml
  • Gastrinoma: facts
    - Originally described by Zollinger and Ellison as the triad of peptic ulcers in unusual locations in the presence of gastric acid hypersecretion and a PET
    - They are the second most common functioning PET but occur with a frequency less than half of insulinoma
    - Peak incidence in the 5th decade of life with slight male predominance
    - Most are sporadic but most common functioning PET in patients with MEN1
  • Insulinoma: Facts
    - Insulinomas are usually less than 2 cm in size (90%) and under 1 cm in size in 40% of cases
    - Usually solitary and occur in equal frequency in the head, body and tail of pancreas
    - When they are malignant they tend to be larger and spread to adjacent nodes
    - CT accuracy is in the 95% range for detection
  • Insulinoma: Facts
    - Most common functioning PET tumor accounting for 40% of all functioning PETs
    - Usually sporadic but account for 10-30% of functioning PETs in patients with MEN1
    - Average age at presentation is 47 years and female to male ratio is 1.4-1
    - Less than 10% are malignant
    - Whipples triad of hypoglycemia, low blood glucose, and relief of symptoms with administraion of glucose
  • Neuroendocrine Tumors of the Pancreas: CT Findings
    - Liver metastases and adenopathy are often hypervascular as well on arterial phase imaging
    - Occassionally venous phase images show the lesion better but this is rare and failure to obtain arterial phase images (25-30 seconds s/p injection) will result in significant false negtive studies
  • Neuroendocrine Tumors of the Pancreas: CT Findings
    - Circumscribed solid masses that displace rather than invade surrounding structures
    - Hypervascular on arterial and venous phase imaging
    - Smaller lesions are more homogeneous and larger lesions more heterogeneous often with cystic degeneration, necrosis and calcification
    - Cystic PETs often have enhancing rims which is a key diagnostic finding (up to 90%) 

    Type of PET

    Average Size

    Most common Location

    Insulinoma

    < 2 cm

    Even distribution throughout gland

    Gastrinoma

    <1 cm if duodenal, 3-4 cm if pancreatic

    Duodenum followed by pancreatic head

    Glucagonoma

    7-8 cm

    Pancreatic tail

    Vipoma

    5-6 cm

    Pancreatic tail

    Somatostatinoma

    5-6 cm

    Pancreatic head

    Nonfunctioning

    5-6 cm

    Even distribution throughout gland

    Type of PET

    Associated Syndrome

    Symptoms

    Insulinoma

    Whipple Triad

    Hypoglycemia, dizziness, vision changes,palpitations

    Gastrinoma

    Zollinger-Ellison syndrome

    Peptic ulcer disease, diarrhea,esophagitis

    Glucagonoma

    4D syndrome (dermatitis,diabetes,DVT. Depression)

    Necrolytic migratory erythema, diabetes, and thromboembolism

    Vipoma

    WDHA syndrome (watery diarrhea, hypokalemia,achlorhydria)

    Profuse watery diarrhea, weight loss, hypokalemia

    Somatostatinoma

    Inhibitory syndrome

    Diabetes, steatorrhea, diarrhea, cholelithiasis

    Nonfunctioning

    none

    Abdominal pain, mass, weight loss or even incidental finding

  • Pancreatic Endocrine Tumors: Facts
    - Prevalence of one in 100,000 people
    - 1-2% of pancreatic tumors
    - Most common in 4th-6th decade of life
    - Half of tumors are non-functioning
    - 99% of PETs are sporadic
  • "Clinically, well differentiated PETs are categorized as those that produce a distinct clinical syndrome (ie, functioning or syndromic tumors) and those that do not (ie, nonfunctioning or nonsyndromic tumors)."

    Pancreatic Endocrine Tumors: Radiologic-Clinicopathologic Correlation
    Lewis RB et al
    RadioGraphics 2010; 30:1445-1464

  • "PETs often have been referred to as islet cell tumors; however, that term is no longer acceptable because of evidence that they do not arise from the islets of Langerhans, but rather from ductal pluripotent stem cells."

    Pancreatic Endocrine Tumors: Radiologic-Clinicopathologic Correlation
    Lewis RB et al
    RadioGraphics 2010; 30:1445-1464

  • Pancreatic Endocrine Tumors: Associated Syndromes
    - Multiple endocrine neoplasia type 1
    - Von Hippel-lindau syndrome
    - Neurofibromatosis type 1
  • Pancreatic Islet Cell Tumors

    - Rare well-differentiated neuroendocrine neoplasm
    - Usually occur sporadically
    - Can be associated with genetic syndromes
    - MEN-1
    - von Hippel-Lindau
    - Neurofibromatosis- 1
    - Tuberous sclerosis
    - 85% occur in pancreas, 15% are ectopic
  • Insulinoma

    - Most common syndromic islet cell tumor
    - Whipple Triad
    - fasting serum glucose levels less than 50mg/dl
    - symptoms of hypoglycemia
    - relief of symptoms after glucose administration
    - Other symptoms
    - palpitations, sweating, and headache, related to catecholamine release
  • Gastrinoma

    - Second most common syndromic islet cell tumor
    - Excess production of gastrin
    - Many will have Zollinger Ellison Syndrome
    - Other symptoms
    - Epigastric pain, peptic ulcer disease, diarrhea
  • Gastrinoma

    - Frequently malignant
    - 30% present with liver metastases
    - CT Appearance
    - Usually multiple and often are located in an extrapancreatic location (gastrinoma triangle)
    - Pancreatic lesions average 3-4 cm in size
    - Hypervascular
  • Glucagonoma

    - Uncommon
    - Typically presents in middle age
    - Most are malignant
    - Patients present with a characteristic migratory rash called necrolytic migratory erythema which usually affects the genitals.
    - Other symptoms: stomatitis, diarrhea, anemia, weight loss, depression and deep vein thrombosis.
    - The syndrome is termed the 4D syndrome (dermatosis, diarrhea, depression and deep vein thrombosis).
  • Glucagonoma

    - Frequently malignant, with approximately 60% of patients presenting with liver metastases
    - Seventy percent of patients present with masses over 5 cm in size
    - Most occur in the body or tail although extrapancreatic glucagonoma has been reported.
    - Most tumors will appear solid and enhancing on CT, but may have low-density areas. Cystic lesions rare
  • Vipoma

    - Secrete a variety of hormones, including vasoactive intestinal peptide (VIP)
    - VIP binds to receptors on the epithelial cells in the intestine, stimulating cAMP production which results in fluid and electrolyte secretion into the lumen, causing a characteristic watery diarrhea.
    - This peptide also inhibits gastrin production, thus resulting in achlorhydria.
    - The syndrome is also referred to as WDHA (Watery Diarrhea, Hypokalemia, and Achlorhydria ).
  • Vipoma

    - Most vipomas are located within the pancreas
    - 75% in the tail
    - Usually over 3 cm in size
    - Almost half of patients will have liver metastases at the time of diagnosis
  • Somatostatinoma

    - Very rare, with less than 200 cases reported in the literature
    - Secrete somatostatin, resulting in diarrhea, cholelithiasis, indigestion and hypochlorhydria
    - About half of patients have metastases at the time of the diagnosis.
  • Somatostatinoma

    - Can occur in the pancreas or duodenum, and both have malignant potential
    - Duodenal tumors are more common at the ampulla of Vater
    - Usually large enough to detect on cross-sectional imaging studies.
    - There is an increased incidence of somatostatinomas in patient with Neurofibromatosis I.
  • Islet Cell Tumors

    - Hypervascular
    - Usually best seen on arterial phase imaging
    - Hypervascular liver mets
    - Sometimes only seen on arterial phase imaging
    - Can range in size from few mm to 10-15cm
    - Do not obstruct ducts (usually).
  • Islet Cell Tumors

    - Treatment
    - Surgical resection
    - Tail ---> distal pancreatectomy
    - Head --> Whipple surgery.
    - Small lesions, especially those which are exophytic can be treated with enucleation, which can be performed laparoscopically.
    - In patients with liver metastases and a symptomatic primary, patients may still benefit from resection of the primary tumor
  • Islet Cell Tumors

    - Treatment
    - Patients with limited liver metastases may benefit from surgical resection of the liver metastases
    - Hepatic artery embolization for control of liver metastases in these patients.
    - Chemoembolization effectively improves clinical symptoms and, in selected patients, may provide sustained tumor control.
    - There is limited data on the use of mechanical ablation (cryotherapy or radiofrequency) of metastatic islet cell neoplasms, but these methods may also be of value.
  • Islet Cell Tumors

    - Treatment
    - Somatostatin analogues such as octreotide, may benefit patients with unresectable or residual disease.
    - Chemotherapy may be used for palliation when ablative techniques have failed or when significant extrahepatic disease is present.
  • "Pancreatic islet cell tumors (ICTs) are neuroendocrine neoplasms that produce and secrete hormones to a variable degree. These neoplasms can present a diagnostic challenge, both clinically and radiologically. ICTs can be classified as either syndromic or nonsyndromic on the basis of their clinical manifestations. Multi-detector row computed tomography (CT) plays an important role in the diagnosis and staging of both syndromic and nonsyndromic ICTs."

    Multidetector Row CT of Pancreatic Islet Cell Tumors
    Horton KM, Hruban Rh, Yeo C, Fishman EK RadioGraphics 2006 March;26(2):453-464.
  • "Pathologic analysis revealed carcinoma in situ in seven patients (19%) and invasive carcinoma in 15 patients (42%) arising from the IPMN. With invasive carcinoma, the size of the tumor in branch duct type and combined type, and the caliber of the main pancreatic duct were significantly larger compared with the lesions without invasive carcinoma (4.7 +/- 1.7 cm vs 2.6 +/- 1.4 cm [p = 0.0007] and 9.3 +/- 5.5 mm vs 4.6 +/- 4.1 mm [p = 0.006], respectively). A solid mass (p < 0.001), dilatation of the common bile duct or common hepatic duct (> or = 15 mm), and the presence of a stent (p = 0.0004) were correlated with the presence of associated invasive carcinoma."
  • Islet Cell Tumors

    - Functioning or hyperfunctioning:
    - Insulinoma most common (47%)
    - Gastrinoma 2nd most common
    - Nonfunctioning
  • Gastrinomas

    - Found in the "gastrinoma triangle" bounded by the porta hepatis and the second and third portions of the duodenum
    - Nearly all gastrinomas are solitary
  • MEN 1 or Wermer Syndrome

    - Synchronous or metachronous tumors of the:
    - Parathyroid glands
    - Anterior pituitary
    - Pancreas
    - GI Tract
  • Pancreatic Islet Cell Tumors

    - Rare well-differentiated neuroendocrine neoplasm
    - Usually occur sporadically
    - Can be associated with genetic syndromes
    - MEN-1
    - von Hippel-Lindau
    - Neurofibromatosis- 1
    - Tuberous sclerosis
    - 85% occur in pancreas, 15% are ectopic
  • Insulinoma

    - Most common syndromic islet cell tumor
    - Whipple Triad
    - fasting serum glucose levels less than 50mg/dl
    - symptoms of hypoglycemia
    - relief of symptoms after glucose administration
    - Other symptoms
    - palpitations, sweating, and headache, related to catecholamine release
  • Gastrinoma

    - Second most common syndromic islet cell tumor
    - Excess production of gastrin
    - Many will have Zollinger Ellison Syndrome
    - Other symptoms
    - Epigastric pain, peptic ulcer disease, diarrhea
  • Gastrinoma

    - Frequently malignant
    - 30% present with liver metastases
    - CT Appearance
    - Usually multiple and often are located in an extrapancreatic location (gastrinoma triangle)
    - Pancreatic lesions average 3-4 cm in size
    - Hypervascular
  • Glucagonoma

    - Uncommon
    - Typically presents in middle age
    - Most are malignant
    - Patients present with a characteristic migratory rash called necrolytic migratory erythema which usually affects the genitals.
    - Other symptoms: stomatitis, diarrhea, anemia, weight loss, depression and deep vein thrombosis.
    - The syndrome is termed the 4D syndrome (dermatosis, diarrhea, depression and deep vein thrombosis).
  • Glucagonoma

    - Frequently malignant, with approximately 60% of patients presenting with liver metastases
    - Seventy percent of patients present with masses over 5 cm in size
    - Most occur in the body or tail although extrapancreatic glucagonoma has been reported.
    - Most tumors will appear solid and enhancing on CT, but may have low-density areas. Cystic lesions rare
  • Vipoma

    - Secrete a variety of hormones, including vasoactive intestinal peptide (VIP)
    - VIP binds to receptors on the epithelial cells in the intestine, stimulating cAMP production which results in fluid and electrolyte secretion into the lumen, causing a characteristic watery diarrhea.
    - This peptide also inhibits gastrin production, thus resulting in achlorhydria.
    - The syndrome is also referred to as WDHA (Watery Diarrhea, Hypokalemia, and Achlorhydria ).
  • Vipoma

    - Most vipomas are located within the pancreas
    - 75% in the tail
    - Usually over 3 cm in size
    - Almost half of patients will have liver metastases at the time of diagnosis
  • Somatostatinoma

    - Very rare, with less than 200 cases reported in the literature
    - Secrete somatostatin, resulting in diarrhea, cholelithiasis, indigestion and hypochlorhydria
    - About half of patients have metastases at the time of the diagnosis.
  • Somatostatinoma

    - Can occur in the pancreas or duodenum, and both have malignant potential
    - Duodenal tumors are more common at the ampulla of Vater
    - Usually large enough to detect on cross-sectional imaging studies.
    - There is an increased incidence of somatostatinomas in patient with Neurofibromatosis I.
  • "The most effective method for revealing insulinomas is a combined imaging protocol that consists of both dual phase thin section multidetector CT and endoscopic sonography."

    CT, Endoscopic Sonography, and a Combined Protocol for preoperative Evaluation of Pancreatic Insulinomas
    Gouya H et al.
    AJR 2003; 181:987-992
  • "The overall diagnostic sensitivity for dual phase helical CT was 94.4% and endoscopic sonography 93.8%. The overall diagnostic sensitivity for combined biphasic thin section helical CT and endoscopic sonography was 100%."

    CT, Endoscopic Sonography, and a Combined Protocol for preoperative Evaluation of Pancreatic Insulinomas
    Gouya H et al.
    AJR 2003; 181:987-992