Glucagonoma and the Glucagonoma Syndrome

Henry William Taylor, MD
The Operative Review of Surgery. 2023; 1:162-167.

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Table of Contents

Pathophysiology
Presentation
Diagnosis
Treatment

Mnemonics
References

Pathophysiology

Also Known as “Glucagon-Secreting Pancreatic Neuroendocrine Tumor”, “Glucagon-Secreting Pancreatic Islet Cell Tumor”, “Pancreatic Islet Alpha Cell Tumor”, “Alpha Cell Neoplasm”, or “Pancreatic Insulin-Producing Tumor”

Definition

  • Glucagon Secreting Neuroendocrine Tumor 1
  • Due to an Abnormal Growth of Alpha Islet-Cells of the Pancreas 2
  • *See Pancreatic Neuroendocrine Tumor (PNET)
  • Extrapancreatic Lesions are Rare (2%) 3
    • Include Kidney, Liver, Duodenum, and Lung 3

Distribution and Size

  • Most Common in the Body and Tail (75%) 2,3
    • Higher Prevalence of Alpha Cells in this Area
  • Average Diameter: 3.6-5.0 cm 3-4

Malignancy

  • Most are Malignant (80-90%) 5
  • 5% Have Metastases at Time of Diagnosis 3
  • Most are Sporadic 2
    • 3-10% Have Multiple Endocrine Neoplasia Type 1 (MEN1) 5-7
    • Rarely Associated with Von Hippel-Lindau Syndrome 2

Epidemiology

  • Average Age: 52-54 Years 2,3
  • 56% are Female 3

Glucagonoma in the Pancreatic Tail 8

Presentation

Symptoms 3,9-11 Mn
  • Weight Loss (60-80%) – Most Common Presenting Symptom
  • Glucose Intolerance/Diabetes (68-95%)
  • Venous Thromboembolism (50%)
  • Inflammation of the Oral Mucosa (Stomatitis), Tongue (Glossitis), or Lips (Cheilitis) (41%)
  • Psychiatric Disorders (20%)
    • Includes Depression, Anxiety, Insomnia, and Psychosis
  • Chronic Diarrhea (14-18%)
Necrolytic Migratory Erythema (NME)
  • Incidence: 70-80% 9-11
    • Not Specific to Glucagonoma and May Present with Other Conditions
  • Characteristic Presentation:
    • Starts as Erythematous Papules of the Face, Perineum, and Extremities
    • Enlarge and Coalesce Over 1-2 Weeks
    • Then Demonstrate Central Clearing with Induration, Blisters, and Crusting
    • Rash is Often Pruritic and Painful
  • Malnutrition and Amino Acid Deficiency Contributes to the Formation 12-14
    • Supplementation (Zinc, Amino Acids, and Fatty Acids) May Help Resolve the Rash 12-14
  • Diagnosis: Skin Biopsy
  • NME Generally Resolves After Tumor Resection 2

Necrolytic Migratory Erythema (NME) 15

Diagnosis

Diagnosis

  • Primary Diagnosis Made by Demonstrating High Fasting Glucagon (> 500 pg/mL) 9,16
  • Biopsy Not Required but Can Be Used for Grading 17

TNM Staging

Localization

  • Initial Imaging: Noninvasive (CT or MRI) 16
  • Somatostatin Receptor Imaging 19-21
    • Consider if Initial Imaging Fails to Localize
    • Options:
      • Somatostatin (Octreotide) Receptor Scintigraphy (SRS) – Classic Test Used
      • Functional PET Scan (Ga-68 DOTATATE) – Becoming More Prevalent with Higher Sensitivity
  • If Noninvasive Imaging Fails: Invasive Imaging
    • Endoscopic Ultrasound (EUS) – Generally Preferred Next Step 22
    • Selective Visceral Angiography – Gold Standard but the Most Invasive 2

PNET on Imaging: (A) CT, (B) EUS, (C) SRS, (D) Functional PET 23

Treatment

Medical Management

  • Measures: 16
    • Glucose Control
    • Somatostatin Analogs (SSAs) to Control Symptoms – Treatment of Choice 24
      • Octreotide or Lanreotide
    • Nutritional Support for Malnutrition – May Require Preoperative Parenteral Nutrition
    • Supplementation of Zinc, Amino Acids, and Fatty Acids to Treat NME 12-14
  • Used Preoperatively or for Patients that are Not Surgical Candidates or in Unresectable Metastatic Disease

Surgical Resection (Treatment of Choice)

  • Definitive Treatment: Surgical Resection 2,16
    • Head/Neck: Pancreaticoduodenectomy
    • Body/Tail: Distal Pancreatectomy (Concurrent Splenectomy if Malignancy is Suspected)
    • Entire Pancreas: Total Pancreatectomy
  • May Consider Enucleation for Small Tumors (< 2-3 cm) – Controversial Due to High Malignancy Rates 11
    • Additional Requirements: Single Lesion, ≥ 2-3 mm From the Main Pancreatic Duct, Well-Encapsulated, and No Local Invasion
  • Due to High Rates of Metastases, Surgical Resection is Most Often Not Feasible 2

Liver-Directed Therapy

  • Resection of Metastases if Able
  • Radiofrequency Ablation (RFA) or Cryoablation 25,26
  • Hepatic Artery Embolization 27,28

Additional Options in Surgically Unresectable Disease

  • Chemotherapy 29-31
  • Radiation Therapy 32,33
    • Pancreatic Neuroendocrine Carcinomas Were Previously Considered to be Resistant to Radiation

Mnemonics

Presentation of Glucagonoma Remembered at the “4-D Syndrome” 34

  • D: Diabetes – Glucose Intolerance
  • D: Dermatosis – Necrolytic Migratory Erythema
  • D: DVT – Venous Thromboembolism
  • D: Depression – Psychiatric Disorders
  • *May Also Consider Diarrhea as an Additional D

References

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  5. Marcal LP, et al. Pancreatic Neuroendocrine Tumors. Oncologic Imaging: A Multidisciplinary Approach, 2e. 2023.
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  11. Li W, Yang X, Deng Y, Jiang Y, Xu G, Li E, Wu Y, Ren J, Ma Z, Dong S, Han L, Ma Q, Wu Z, Wang Z. Necrolytic migratory erythema is an important visual cutaneous clue of glucagonoma. Sci Rep. 2022 May 31;12(1):9053.
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