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Internal Medicine

Pancreatic neuroendocrine tumors (PanNETs)

Introduction

Pancreatic neuroendocrine neoplasms are a cancer of neuroendocrine cells that are within the pancreas.

Neuroendocrine neoplasms arising from cells of the endocrine (hormonal) and nervous system within the pancreas.

  • Also known as “islet cell tumors“

Epidemiology

Classification

  • Non-functional (non hormone-secreting) tumours (common)
  • Functional (hormone-secreting) tumours (less common)
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Cellular classifications of pancreatic neuroendocrine tumors (islet cell tumors) | Lairmore, T. C., Quinn, C. E., & Martinez, M. J. (2013). Neuroendocrine tumors of the pancreas: molecular pathogenesis and current surgical management. Translational Gastrointestinal Cancer; Vol 3, No 1 (January 2014): Translational Gastrointestinal Cancer. Retrieved from http://tgc.amegroups.com/article/view/2774
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Nomenclature, incidence, location and malignancy of pancreatic NETs | Lairmore, T. C., Quinn, C. E., & Martinez, M. J. (2013). Neuroendocrine tumors of the pancreas: molecular pathogenesis and current surgical management. Translational Gastrointestinal Cancer; Vol 3, No 1 (January 2014): Translational Gastrointestinal Cancer. Retrieved from http://tgc.amegroups.com/article/view/2774

Functional (hormone-secreting) tumours:

  • β-cells → Insulinoma
  • G-cells → Gastrinoma → Zollinger Ellison syndrome → ↑↑↑ HCl:
    • ↑↑↑ HCl → Peptic ulcer in stomach, duodenum & jejunum
    • ↑↑↑ HCl → Inactivates pancreatic digestive enzymes → steatorrhoea
  • D1-cells → Vasoactive intestinal polypeptidinoma (VIPoma) → WDHA (watery diarrhoea, hypokalemia, achlorhydria) syndrome
  • α-cells → Glucagonoma:
    • ↑↑ Glucose → Diabetes mellitus
    • ↓↓ Lipids → Necrolytic migratory erythema
  • δ-cells → Somatostatinoma → â†‘↑ Somatostatin:
    • ↑↑ Somatostatin → â†“↓ Insulin → Diabetes mellitus
    • ↑↑ Somatostatin → ↓↓ Gastrin → Steatorrhoea
    • ↑↑ Somatostatin → ↓↓ VIP → Hypochlorhyrdria
  • Very rare: Pancreatic polypeptide cells & enterochromaffin cells

Aetiology

Genetic mutations:

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Germline mutations in the menin tumor suppressor gene may represent missense, nonsense, deletion, or RNA splicing defects and are distributed anywhere along the 9 coding exons and the intron-exon junctions of the gene. | Mutch MG et al. Human mutation 1999;13:175-85 (53).
  • MEN1 mutation → Multiple endocrine neoplasia (MEN) Type 1 (tumours in parathyroid, pituitary & pancreas)
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Common Genes: PNET vs Pancreatic Adenocarcinoma (PDAC) | Enets. (2019) Pancreatic Neuroendocrine Tumors: State-of-the-Art Diagnosis and Management: Page 3 of 3 | Cancer Network. Retrieved December 30, 2019, from https://www.cancernetwork.com/neuroendocrine-tumors/pancreatic-neuroendocrine-tumors-state-art-diagnosis-and-management/page/0/2

Pathophysiology

Hallmarks of pNET:

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The hallmarks of pNET. | Hanahan and Weinberg, Hallmarks of cancer: the next generation. Cell 2011;144:646–74 (9), © 2011 Elsevier Inc.

Insulinoma:

β-cells → Insulinoma
  • Whipple’s triad (diagnostic hallmark):
    • Hypoglycemia symptoms (provoked by fasting)
    • Glucose < 50mg/dl (at time of presentation)
    • Relief of symptoms on glucose administration

Gastrinoma:

G-cells → Gastrinoma → Zollinger Ellison syndrome → ↑↑↑ HCl:
  • ↑↑↑ HCl → Peptic ulcer in stomach, duodenum & jejunum
  • ↑↑↑ HCl → Inactivates pancreatic digestive enzymes → steatorrhoea

Vasoactive intestinal polypeptidinoma (VIPoma):

D1-cells → VIPoma
  • WDHA (watery diarrhoea, hypokalemia, achlorhydria) syndrome

Glucagonoma:

α-cells → Glucagonoma
  • ↑↑ Glucose → Diabetes mellitus
  • ↓↓ Lipids → Necrolytic migratory erythema

Somatostatinoma:

δ-cells → Somatostatinoma → ↑↑ Somatostatin
  • ↑↑ Somatostatin → ↓↓ Insulin → Diabetes mellitus
  • ↑↑ Somatostatin → ↓↓ Gastrin → Steatorrhea
  • ↑↑ Somatostatin → ↓↓ VIP → Hypochlorhydria

Clinical features

Common functional pNETs and their syndromes | Reynolds, R. B., & Folloder, J. (2014). Clinical Management of Pancreatic Cancer. Journal of the Advanced Practitioner in Oncology, 5(5), 356–364. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26114016

Diagnosis

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WHO histologic grading (2010):

2010 WHO grading system for pNETs

TNM staging:

Management

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Treatment Algorithm. Suggested treatment algorithm for pancreatic neuroendocrine tumors, based on functionality and localized or metastatic disease. | Authors Links. (2019) Cancers | Free Full-Text | Treatment Options for Pancreatic Neuroendocrine Tumors | HTML. Retrieved December 30, 2019, from https://www.mdpi.com/2072-6694/11/6/828/htm#
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Summary of all surgical options available to deal with PanNETs. A tailored, single-patient, focused approach remains the best option. | Lairmore, T. C., Quinn, C. E., & Martinez, M. J. (2013). Neuroendocrine tumors of the pancreas: molecular pathogenesis and current surgical management. Translational Gastrointestinal Cancer; Vol 3, No 1 (January 2014): Translational Gastrointestinal Cancer. Retrieved from http://tgc.amegroups.com/article/view/2774
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Management of pancreatic neuroendocrine tumors: enucleation vs. pancreatic resection. Depicted on the left is enucleation of a small, apparently benign solitary insulinoma of the pancreatic tail. On the right is shown a pancreaticoduodenectomy specimen for a large malignant NET of the head of the pancreas. | Lairmore, T. C., Quinn, C. E., & Martinez, M. J. (2013). Neuroendocrine tumors of the pancreas: molecular pathogenesis and current surgical management. Translational Gastrointestinal Cancer; Vol 3, No 1 (January 2014): Translational Gastrointestinal Cancer. Retrieved from http://tgc.amegroups.com/article/view/2774

Summary

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