Glucagonoma

Glucagonomas are pancreatic neuroendocrine tumors that produce excessive amounts of glucagon and are associated with a distinctive clinical syndrome. Glucagonomas have a very high malignant potential.

Epidemiology

Incidence – <1/1,000,000
Age – median age is 50s-60s
Sex – M:F, equal
Occurrence – third most common functional neuroendocrine tumor

Risk Factors

Usually sporadic
Genetic – rarely associated with genetic variations; however, patients diagnosed with MEN1 or von Hippel-Lindau syndrome are at higher risk for glucagonomas

Pathophysiology

Tumor of the alpha cells of the pancreatic islets (97%); small number in proximal duodenum
- Most frequently malignant, calcified, and located in the body and tail of the pancreas with regional node involvement
- Secretes excessive amounts of glucagon – stimulates glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, and insulin secretion
Tumor is usually large (5-10 cm) when discovered; typically a single tumor is found

Clinical Presentation

Diabetes mellitus
Glossitis, stomatitis, angular cheilitis
Panhypoaminoaciduria
Skin rash
- Migratory necrolytic erythema
- Starts as annular erythema at intertriginous sites
- Progresses to papulobullous stage that waxes and wanes
Increased risk of deep-vein thrombosis
Diarrhea
Weight loss
Frequently metastatic at presentation
- Liver is the most common site of metastasis, followed by lymph nodes or bones

Treatment

Symptomatic relief
Somatostatin analogues
Resection – patients typically present at advanced stage; however, tumor usually has indolent behavior

Indications for Testing

Neuroendocrine symptoms compatible with tumor site; pancreatic tumor with neuroendocrine symptoms

Laboratory Testing

Glucagon – level >500 pg/mL is highly suggestive of glucagonoma
CBC – nonspecific, but 90% have normocytic anemia

Histology

Tumor size >5 cm associated with malignancy in 60-80% of cases
Nested or trabecular arrangement of small- to medium-sized cells
- Finely granular eosinophilic cytoplasm
- Central round-to-oval nuclei
- Stippled chromatin (“salt and pepper”)
Immunohistochemistry – chromogranin A, synaptophysin, glucagon are most valuable
- Other stains include neuron specific enolase polyclonal (NSE P), pan cytokeratin (AE1,3), protein gene product (PGP) 9.5

Imaging Studies

Multiphasic contrast enhanced CT or MRI – diagnostic for tumor
- If negative, proceed to scintography for tumor identification
Somatostatin-receptor scintigraphy (Indium-111 OctreoScan^®) may help localize small lesions

Differential Diagnosis

Skin rash
- Psoriasis
- Paraneoplastic syndromes
- Vitamin deficiency syndromes (pellagra)
- Toxic epidermal necrolysis
- Pemphigus
- Pemphigoid
- Herpes
- Seborrheic/contact dermatitis
Hyperglycemia
- Diabetes mellitus (type 1 or type 2)
- Metabolic syndrome
Deep vein thrombosis
- Thrombophilia
Other malignancy
- Pancreatic adenocarcinoma

Tests generally appear in the order most useful for common clinical situations

Test name: Glucagon

ARUP #: 0099165

Methodology: Quantitative Radioimmunoassay

Use:

Diagnose glucagonoma

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Nonspecific testing in glucagonoma evaluation

May show normocytic anemia

Test name: Chromogranin A by Immunohistochemistry

ARUP #: 2003830

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of glucagonoma