Glucagonoma
Summary
Glucagonoma is a rare functioning neuroendocrine tumour arising from pancreatic alpha-cells that produces excess Glucagon. It typically presents with the classic Glucagonoma Syndrome: The "4 Ds" – Dermatosis (Necrolytic Migratory Erythema), Diabetes Mellitus, Deep Vein Thrombosis, and Depression. The characteristic rash, Necrolytic Migratory Erythema (NME), is often the presenting feature and is virtually pathognomonic. Glucagonomas are usually large (>4cm) and malignant (~60-70% have metastases at diagnosis), most commonly located in the pancreatic tail. Treatment is surgical resection if possible, with Somatostatin Analogues for symptom control. [1,2]
Clinical Pearls
The 4 Ds: Dermatosis (NME), Diabetes, DVT, Depression. This is the classic exam mnemonic for Glucagonoma syndrome.
Necrolytic Migratory Erythema (NME): A distinctive, migratory, blistering, erythematous rash, typically affecting the perineum, groin, buttocks, and lower limbs. It is often misdiagnosed as eczema, psoriasis, or cellulitis for years. Any unexplained NME should prompt serum Glucagon measurement.
Usually Malignant at Diagnosis: Unlike Insulinoma (mostly benign), Glucagonomas are often large and metastatic when discovered. Early diagnosis is critical.
Zinc Deficiency: The NME rash is thought to be related to the catabolic effects of glucagon causing amino acid and Zinc depletion. Zinc supplementation may improve the rash.
Demographics
- Incidence: Extremely rare (~1 in 20 million per year). One of the rarest PNETs.
- Age: Usually 40-70 years.
- Sex: Slightly more common in females.
Location
- Pancreatic Tail/Body: 60-80%. (Alpha cells are more concentrated in tail.)
- Malignancy: 50-80% have metastases (liver, lymph nodes) at diagnosis.
Associations
| Condition | Notes |
|---|---|
| MEN1 | ~3-5% associated with MEN1 syndrome. Screen for family history and other MEN1 features (Hyperparathyroidism, Pituitary adenoma). |
Mechanism of Glucagonoma Syndrome
- Alpha-Cell Tumour: Tumour arises from glucagon-secreting alpha-cells of pancreatic islets.
- Hypersecretion of Glucagon: Sustained high glucagon levels.
- Catabolic State: Glucagon promotes glycogenolysis, gluconeogenesis (from amino acids), lipolysis.
- Hyperglycaemia (Diabetes): Increased hepatic glucose output. Usually mild-moderate DM.
- Hypoaminoacidaemia: Amino acids are used for gluconeogenesis. Leads to protein malnutrition.
- Zinc and Fatty Acid Deficiency: Contributes to NME rash and other skin/mucosal changes.
- Hypercoagulability: Glucagon may directly activate coagulation pathways or cause endothelial dysfunction. High risk of VTE.
- Weight Loss/Cachexia: Catabolic effects lead to significant weight loss.
- Neuropsychiatric Effects: Depression, cognitive changes.
| Condition | Key Features |
|---|---|
| Glucagonoma | NME + Diabetes + DVT + Weight loss. High serum Glucagon. Pancreatic mass. |
| Acrodermatitis Enteropathica | Zinc deficiency (from diet or malabsorption). Similar NME-like rash. Low serum Zinc. No pancreatic mass. |
| Essential Fatty Acid Deficiency | Skin changes similar to NME. TPN-related or severe malnutrition. |
| Pellagra (Niacin Deficiency) | Dermatitis + Diarrhea + Dementia. Sun-exposed areas. |
| Psoriasis / Intertrigo | May mimic early NME. No migratory pattern. |
| Cellulitis / Erysipelas | Localised infection. Fever. Not migratory. |
Glucagonoma Syndrome: The "4 Ds" (and more)
| Feature | Prevalence | Notes |
|---|---|---|
| Necrolytic Migratory Erythema (NME) | 70-80% | Pathognomonic. Red, scaly, blistering rash. Migrates. Heals centrally (ring-like). Sites: Perineum, Groin, Buttocks, Lower Limbs, Perioral. |
| Diabetes Mellitus | 70-90% | Usually mild. Rarely requires high-dose insulin. |
| Deep Vein Thrombosis (DVT) / PE | 30-50% | Hypercoagulable state. Major cause of morbidity/mortality. |
| Depression / Neuropsychiatric | 20-40% | Depression, apathy, cognitive impairment. |
| Weight Loss / Cachexia | 60-80% | Significant. Due to catabolic state. |
| Stomatitis / Glossitis | 30-40% | Sore, red tongue and mouth. Angular cheilitis. |
| Diarrhea | 15-30% | Secretory. |
| Anaemia (Normocytic) | 30-50% | Multifactorial. |
NME Rash Description
Biochemistry
| Test | Finding |
|---|---|
| Fasting Serum Glucagon | Markedly Elevated (>500 pg/mL, often >1000 pg/mL). Normal less than 100 pg/mL. Diagnostic. |
| Fasting Glucose / HbA1c | Elevated (Diabetes). |
| Zinc Level | Often low. |
| Amino Acids | Low (Hypoaminoacidaemia). |
| FBC | Normocytic anaemia. |
| D-Dimer / Coagulation Screen | May be abnormal (hypercoagulability). |
Imaging (Localisation)
| Modality | Notes |
|---|---|
| CT Abdomen (Triple Phase) | First-line. Glucagonomas are usually large (>4cm) and easily seen. Enhancing pancreatic tail mass. Assess for liver metastases. |
| MRI Abdomen | Alternative. Good for liver lesion characterisation. |
| 68Ga-DOTATATE PET-CT | Functional imaging. High sensitivity for somatostatin receptor positive tumours. Staging and detecting metastases. |
| EUS | Less commonly needed as tumours are usually large. Can be used for biopsy. |
Skin Biopsy (NME)
- Shows: Necrosis of superficial epidermis, detached keratinocytes, psoriasiform hyperplasia.
- Non-specific but supportive if clinical suspicion.
Management Algorithm
SUSPECTED GLUCAGONOMA
(NME + Diabetes + Weight Loss + DVT)
↓
FASTING SERUM GLUCAGON
(Markedly Elevated = Diagnostic)
↓
LOCALISATION IMAGING
(CT / MRI / DOTATATE PET)
↓
STAGING: LOCALISED vs METASTATIC
┌────────────────┴────────────────┐
LOCALISED METASTATIC
↓ ↓
SURGICAL RESECTION SOMATOSTATIN ANALOGUES
(Distal Pancreatectomy) (Octreotide / Lanreotide)
+ - Controls symptoms (NME, Diabetes)
SYMPTOM CONTROL - Anti-tumour effect (PRRT option)
(Pre-op Octreotide, +/- LIVER-DIRECTED THERAPY
DVT Prophylaxis) (Embolisation, Ablation)
↓ +/- SYSTEMIC THERAPY
CURE POSSIBLE (Everolimus, Sunitinib, Chemo)
↓
ALL PATIENTS:
- Anticoagulation (DVT prophylaxis/treatment)
- Zinc Supplementation
- Nutritional Support (Amino Acids, TPN if severe)
- Skin Care (Emollients)
- MEN1 Screening
Medical Management
| Agent | Purpose |
|---|---|
| Somatostatin Analogues (Octreotide LAR, Lanreotide) | First-line medical therapy. Inhibits glucagon secretion. Improves NME rash and symptoms. Also has anti-tumour effect. |
| Anticoagulation | DVT prophylaxis (LMWH) and treatment if VTE develops. Critical. |
| Zinc Supplementation | May improve NME rash. |
| Amino Acid Infusion / TPN | For severe malnutrition. Improves NME. |
| Targeted Therapy (Everolimus, Sunitinib) | For progressive/metastatic disease. |
| PRRT (Lutetium-DOTATATE) | For somatostatin receptor positive metastatic disease. |
Surgical Management
- Distal Pancreatectomy +/- Splenectomy: Standard for tumours in pancreatic body/tail (most glucagonomas).
- Curative if localised: But most have metastases at diagnosis.
- Debulking surgery: May be considered even with metastases for symptom control.
| Complication | Notes |
|---|---|
| Venous Thromboembolism (DVT/PE) | Major cause of morbidity and mortality. Occurs in 30-50%. |
| Metastatic Disease | ~60% have liver metastases at diagnosis. |
| Severe Malnutrition / Cachexia | Due to catabolic effects of glucagon. |
| Diabetes Complications | Usually mild DM, but can develop. |
| Skin Infections | Secondary infection of NME lesions. |
- Overall 5-Year Survival: ~50-60% (due to high rate of malignancy at diagnosis).
- Localised, Resected: Better prognosis, 80%+ 5-year survival.
- Metastatic Disease: Median survival 3-5 years with treatment.
- Somatostatin Analogues: Improve quality of life and may slow tumour growth.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Pancreatic NETs | ENETS / NANETS | Glucagon levels, imaging, Somatostatin Analogues. |
| Functional PNETs | Endocrine Society | Biochemical diagnosis, surgical resection when feasible. |
Landmark Evidence
- Glucagonoma syndrome was first described by Mallinson in 1974.
- Somatostatin analogues: Multiple studies showing symptomatic improvement and disease stabilisation.
What is a Glucagonoma?
It is a very rare tumour in the pancreas that makes too much of a hormone called glucagon. Glucagon is normally used to raise blood sugar levels when they are low. When there is too much glucagon, it causes problems like a distinctive skin rash, diabetes, weight loss, and a tendency to form blood clots.
What is the rash?
The rash is called Necrolytic Migratory Erythema. It appears as red, blistering patches, usually around the groin, buttocks, and legs. It tends to move around the body. It is often what leads doctors to suspect this condition.
How is it treated?
If the tumour can be removed surgically, that is the best treatment. If it has spread, we can use injections (Somatostatin Analogues) to control the symptoms and slow the tumour down. We also give blood thinners to prevent clots.
Primary Sources
- Mallinson CN, et al. A glucagonoma syndrome. Lancet. 1974;2:1-5. PMID: 4134233.
- Jensen RT, et al. ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms: Functional Pancreatic Neuroendocrine Tumour Syndromes. Neuroendocrinology. 2012;95:98-119.
Common Exam Questions
- Diagnosis: "Migratory blistering rash + New Diabetes + DVT. Diagnosis?"
- Answer: Glucagonoma.
- Rash Name: "What is the pathognomonic rash?"
- Answer: Necrolytic Migratory Erythema (NME).
- Mnemonic: "What are the 4 Ds?"
- Answer: Dermatosis, Diabetes, DVT, Depression.
- Location: "Where in the pancreas is glucagonoma usually found?"
- Answer: Tail (Alpha cells concentrated there).
Viva Points
- Compare Insulinoma vs Glucagonoma: Insulinoma = Small, benign, fasting hypoglycaemia. Glucagonoma = Large, often malignant, hyperglycaemia, NME rash.
- Why NME occurs: Hypoaminoacidaemia and Zinc deficiency from catabolic effects of glucagon.
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