Pancreatic Neuroendocrine Tumors (PanNETs)

Pancreatic neuroendocrine tumors (PanNETs) arise from the endocrine pancreas (islet cells) and represent 2%–5% of primary pancreatic neoplasms; the other 95%–98% of pancreatic neoplasms are from the exocrine pancreas. The majority of PanNETs are nonfunctional (50%–75%), while others that are functional may be benign or malignant. Benign or malignant PanNETs include insulinomas, gastrinomas, malignant pancreatic neuroendocrine carcinomas, and very rare tumors named glucagonomas, somatostatinomas, and VIPomas, after the hormones they secrete. Diagnosis is made clinically, with lab testing for hormone secretion, as well as imaging or upper endoscopy. Management is surgical or with newer molecularly targeted therapies.

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Overview

Epidemiology

  • Rare; annual incidence: ≤ 1 case/100,000 
  • 2%–3% of all pancreatic tumors arise from the endocrine pancreas and are called pancreatic neuroendocrine tumors (PanNETs):
    • Resemble neuroendocrine tumors (NETs) elsewhere in the alimentary tract
    • Benign and malignant tumors
    • May produce pancreatic hormones (e.g., insulin, glucagon, gastrin) or be nonfunctional
  • Most commonly diagnosed between ages 30 and 50
  • Also called islet cell tumors

Etiology

  • Most PanNETs are sporadic.
  • 50%–75% are nonfunctioning (i.e., not associated with a hormonal syndrome).
  • In hereditary endocrinopathies:
    • Tumors have a more indolent course.
    • Syndromes that can be involved and percentage that develop PanNET in their lifetime 
      • MEN 1: 80%–100% 
      • Von Hippel–Lindau (VHL) syndrome: 20%
      • Neurofibromatosis type I (NF1): 10%
      • Tuberous sclerosis: 1%
  • Other potential risk factors, with weaker scientific evidence than hereditary causes:
    • Smoking
    • Diabetes
    • Chronic pancreatitis
    • Alcohol use disorder

Pathology and Pathophysiology

Pathology

  • Except for insulinomas, > 50% are malignant.
  • Morphology resembles neuroendocrine tumors found elsewhere in the alimentary tract:
    • Sites: 
      • Anywhere in the pancreas or in immediate peripancreatic tissues
      • May be single or multiple
      • Gastrinoma triangle (most gastrinomas): duodenum > pancreas > extrapancreatic tissues
    • Microscopic features of well-differentiated neuroendocrine tumors:
      • Architecture: solid nests, trabeculae, glandular, acinar
      • Cytology: small-to-medium cells, round nuclei with “salt-and-pepper” (finely stippled) chromatin, low mitotic index
    • Microscopic features of poorly differentiated neuroendocrine carcinomas:
      • Architecture: sheets or nests of atypical cells
      • Cytology: pleomorphic, hyperchromatic nuclei, mitotic figures
      • Higher proliferation index (more mitoses or ≥ 3% nuclei expressing Ki-67): tend to be aggressive
      • The only valid criteria for malignancy are metastases, vascular invasion, and local infiltration.

Pathophysiology

3 of the most common somatic mutations:

  • MEN 1: the same mutation seen in hereditary MEN 1, remembered as the “3 Ps”: 
    • Parathyroid hyperplasia or adenoma
    • Pituitary adenoma from anterior pituitary (usually prolactinoma)
    • PanNETs (gastrinoma, insulinoma, glucagonoma, VIPoma)
  • PTEN, TSC2: tumor suppressor genes that cause activation of the oncogenic mTOR signaling pathway
  • ATRX, DAXX: allow telomeres to be maintained in neoplastic cells

Clinical Presentation and Diagnosis

Clinical presentation

  • If nonfunctional (50%–75%) → diagnosis made by mass effect or presence of metastases
  • If functional (hormone secreting) → characteristics of the syndrome related to the elevated hormone produced
  • The 4 most common and distinctive functional PanNETs:
    • Insulinoma (beta cell tumors): the most common functional PanNET
      • Hyperinsulinism and recurrent hypoglycemic episodes
      • Most insulinomas are solitary.
      • 10% associated with MEN 1
      • 90% benign
    • Gastrinoma: 
      • Fasting hypergastrinemia and Zollinger–Ellison syndrome (ZES)
      • Usually multiple and located in the duodenal wall
      • Hypersecretion of gastric acid and peptic ulcers (in stomach, duodenum)
      • 25% associated with MEN 1
      • 60%–90% are malignant.
      • EGD shows multiple ulcers and thick gastric folds.
    • Glucagonoma (alpha cell tumor):
      • Excess glucagon causes watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome)
      • Most glucagonomas present with hepatic metastases.
    • VIPoma:
      • Produce vasoactive intestinal peptide (VIP) and present with watery diarrhea
      • Most are solitary.
      • Approximately 50% have hepatic metastases.
    • Rare functional PanNETs: 
      • Somatostatinomas: cause diabetes mellitus, cholelithiasis, steatorrhea, and hypochlorhydria
      • Carcinoid tumors: produce serotonin and carcinoid syndrome 
      • 2 or more hormones secreted: Besides insulin, glucagon, and gastrin, PanNETs may produce adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), serotonin, and norepinephrine.

Diagnosis

Patients may present with metastatic disease in the liver, which is then confirmed with biopsy. The diagnostic approach focuses on identifying both the extent of disease spread and the likely primary site of disease. 

  • Imaging: 
    • Multiphasic CT or MRI of the abdomen
    • Nuclear medicine imaging using radiolabeled somatostatin analogs
    • If available, functional imaging with gallium PET scan
    • Endoscopic ultrasonography (EUS) if not found on other imaging
    • An octreotide scan (mimics natural somatostatin pharmacologically) detects somatostatin receptor expression.
  • Lab testing:
    • Hormone secretion for PanNETs
    • Peptide markers may be used in the follow-up of patients with pancreatic NETs:
      • Chromogranin A (CgA)
      • Pancreatic polypeptide (PP)
Solitary insulinoma in the head of the pancreas CT

Contrast-enhanced CT (transverse section) showing a solitary insulinoma in the head of the pancreas (arrow)

Image: “Insulinoma presenting as refractory seizure disorder” by Correia P, Panchani R, Ranjan R, Agrawal C. License: CC BY 3.0, edited by Lecturio.

Management

In general, management is surgical if the neoplasm is resectable.

  • Malignant or unresectable PanNETs: various treatments
    • Long-acting analogs of somatostatin: octreotide, lanreotide 
    • Debulking/resection of local and metastatic tumors
    • Radiation therapy (RT) and radiolabeled peptide receptor radionuclide therapy 
    • Hepatic artery embolization
    • Radiofrequency ablation (RFA) and cryoablation
    • Radioembolization
    • Liver transplantation
    • Chemotherapy: 
      • Only modest response with conventional cytotoxic chemotherapy
      • Newer molecularly targeted therapies are used.
  • Insulinoma:
    • Surgery if resectable tumor (90%)
    • Only 10% of insulinomas are malignant; most other PanNETs are malignant.
    • Unresectable tumors: diazoxide (inhibits insulin release) 
  • Gastrinoma: 
    • Proton pump inhibitors (PPIs): used to control the symptoms
    • Surgery: Whipple procedure if no hepatic metastases
  • VIPoma:
    • Correct fluid and electrolyte abnormalities (dehydration, hypokalemia)
    • Surgery is possible in only approximately ½ of the cases.
  • Glucagonoma:
    • Nutritional support for patients with weight loss and nutritional deficiency
    • Octreotide/lanreotide can improve skin rash, weight loss, pain, and diarrhea.

Differential Diagnosis

Differential diagnosis of pancreatic masses

  • Invasive pancreatic ductal adenocarcinoma (PDAC): arises from the ductal cells of the exocrine pancreas. Clinical presentation includes symptoms of abdominal pain, jaundice, and weight loss. Diagnosis is made by CT, MRI, and EUS. Management by surgical resection, usually with neoadjuvant or adjuvant chemotherapy, provides the only chance for a cure in the 15%–20% of patients who have resectable disease at the time of diagnosis. Other rare malignant tumors arising from the exocrine pancreas are acinar cell carcinoma and pancreatoblastoma.
  • Acinar cell carcinoma: a rare primary malignant exocrine gland tumor that produces exocrine enzymes such as trypsin and lipase. Acinar cell carcinomas can cause a metastatic fat necrosis syndrome due to lipase release in the circulation. Such malignancies can occur in children, and there is a better prognosis than with PDAC.
  • Pancreatoblastoma: a rare primary malignant exocrine gland tumor seen mostly in children. The histology shows multiple lines of differentiation (acinar, ductal, mesenchymal, neuroendocrine) and squamoid nests mixed with acinar cells. The prognosis is relatively good.

Differential diagnosis of insulinoma

  • Factitious hypoglycemia: may result from exogenous self-administration of insulin. Factitious hypoglycemia is often seen with healthcare workers who present with symptoms of hypoglycemia. Unlike with insulinomas, a laboratory evaluation will reveal low C peptide and proinsulin levels despite high insulin levels. Management includes psychiatric therapy and correcting hypoglycemia.
  • Sulfonylurea toxicity: may occur in patients who are not eating or have renal impairment. Patients will present with hypoglycemia. Unlike with insulinomas, serum sulfonylurea testing will be positive. Management includes the withdrawal of the causative agent and treatment for hypoglycemia.

Differential diagnosis of gastrinoma and glucagonoma

  • Peptic ulcer disease (PUD): ulceration of the mucosal lining of the stomach or duodenum, most commonly due to infection with Helicobacter pylori or use of NSAIDs. The most common symptom of both duodenal and gastric ulcers is epigastric pain. Diagnosis is made by endoscopy. Sporadic peptic ulcers usually respond well to treatment regimens with antibiotics and PPIs.
  • VIPoma: neuroendocrine tumor secreting VIP. VIPoma is also associated with MEN 1. The tumor causes chronic diarrhea, flushing, and wheezing. Diagnosis is established by measuring blood and urine levels of VIP. Treatment consists of surgical tumor removal and symptom management.

References

  1. Strosberg, JR. (2021). Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms. UpToDate. Retrieved July 19, 2021, from https://www.uptodate.com/contents/classification-epidemiology-clinical-presentation-localization-and-staging-of-pancreatic-neuroendocrine-neoplasms
  2. Jensen, R. (2018). Neuroendocrine tumors of the gastrointestinal tract and pancreas. In Jameson, J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine. 20th ed. Vol 1. pp. 596–616. McGraw-Hill Education. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192104918
  3. American Society of Clinical Oncology (ASCO). (2019). Neuroendocrine tumor of the pancreas: Risk factors. Cancer.Net. Retrieved November 17, 2020, from https://www.cancer.net/cancer-types/neuroendocrine-tumor-pancreas/risk-factors

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