What is a Glucagonoma?

A glucagonoma is a rare pancreatic neuroendocrine tumor (NET) that secretes excessive glucagon, leading to a characteristic syndrome of diabetes, weight loss, and a distinctive skin rash called necrolytic migratory erythema (NME).

Key Facts:

• Extremely Rare: ~1 in 20 million per year
• Location: Pancreas (usually tail)
• Size: Often large at diagnosis (>5 cm)
• Malignant in 50-80%: Often metastatic at diagnosis (liver)
• Peak Age: 50-70 years

How Does High Glucagon Cause Symptoms?

• Glucagon: Hormone that raises blood sugar (opposes insulin)
• Effects of Excess Glucagon:
  • Hyperglycemia → diabetes mellitus
  • Increased protein breakdown → weight loss, muscle wasting
  • Hypoaminoacidemia (low amino acids) → skin rash (necrolytic migratory erythema)
  • Increased lipolysis

Classic Triad ("The 4 D's"):

1. Dermatitis (Necrolytic Migratory Erythema): Characteristic rash
2. Diabetes Mellitus: Mild diabetes
3. Deep Vein Thrombosis (DVT): Blood clots
4. Depression, Weight Loss (Decline)

Symptoms:

1. Necrolytic Migratory Erythema (NME) - PATHOGNOMONIC (67-90%):

• Appearance: Red, blistering rash → crusting, scaling, central healing with hyperpigmentation
• Distribution: Perineum, groin, buttocks, lower abdomen, legs, face (perioralmost characteristic)
• Cyclical: Lesions come and go, migrate
• Painful, Itchy
• Often mistaken for eczema, psoriasis, or fungal infection initially

2. Diabetes Mellitus (80-90%):

• Usually mild (fasting glucose 120-200 mg/dL)
• Easy to control

3. Weight Loss (70-90%):

• Severe, progressive
• Muscle wasting, cachexia

4. Thromboembolic Events (20-50%):

• Deep vein thrombosis (DVT), pulmonary embolism (PE)
• Increased clotting risk from tumor

5. Other Symptoms:

• Diarrhea (15-30%)
• Glossitis, Cheilitis: Inflammation of tongue, lips
• Brittle Nails
• Depression, Psychiatric Symptoms
• Normocytic Normochromic Anemia

Diagnosis:

1. Serum Glucagon:

• Normal: <50-100 pg/mL
• Glucagonoma: Typically >1000 pg/mL (often 1000-10,000)
• Markedly Elevated Glucagon is Diagnostic
• Other Causes of Mild Elevation (100-500 pg/mL): Cirrhosis, chronic kidney disease, critical illness, starvation, glucocorticoids

2. Imaging (Localize Tumor, Assess Metastases):

• CT or MRI Abdomen: Usually large pancreatic mass (>5 cm), liver metastases common
• Gallium-68 DOTATATE PET/CT: Somatostatin receptor imaging

3. Skin Biopsy (NME):

• Necrolysis in upper epidermis (hallmark finding)

4. Labs:

• Fasting Glucose, HbA1c: Assess diabetes
• Hypoaminoacidemia: Low plasma amino acids
• Hypoalbuminemia, Anemia
• Chromogranin A: Tumor marker (usually elevated)

Treatment:

1. Surgery (If Resectable):

• Tumor Resection ± Metastasectomy: Curative if all tumor removed
• Debulking Surgery: Even if metastatic—reduces hormone levels, improves symptoms (especially rash)
• Note: Many patients have metastases (liver) at diagnosis

2. Somatostatin Analogs (SSAs) - FIRST-LINE for Symptom Control:

• Octreotide (Sandostatin LAR®), Lanreotide (Somatuline®)
• Effects:
  • Suppress glucagon secretion
  • Dramatic improvement in rash (often complete resolution)
  • Slow tumor growth
• Dosing: Long-acting monthly injections

3. For Metastatic/Unresectable Disease:

• Peptide Receptor Radionuclide Therapy (PRRT): Lutetium-177 DOTATATE (Lutathera®)
• Everolimus (Afinitor®): mTOR inhibitor; slows tumor progression
• Chemotherapy: Streptozocin-based regimens (relatively resistant to chemo)
• Liver-Directed Therapies: Embolization, RFA, radioembolization for liver mets

4. Supportive/Symptomatic Treatment:

• Nutritional Support:
  • High-protein diet
  • Amino acid supplementation (may improve rash)
  • Zinc supplementation
• Diabetes Management: Usually easy to control with diet, metformin, or low-dose insulin
• Anticoagulation: If DVT/PE develops (or prophylaxis if high risk)
• Skin Care: Gentle cleansers, emollients for rash

Prognosis:

• Slow-Growing Tumors: Even metastatic disease progresses slowly
• 5-Year Survival:
  • Localized: 50-70%
  • Metastatic: 30-50%
• Many patients live for years with metastatic disease
• Symptom control (especially rash) greatly improves quality of life