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FeedbackGlucagonomas are a type of pancreatic neuroendocrine tumor (PNET) that produce excessive amounts of glucagon, which causes glucose intolerance, weight loss, and a distinctive rash (migratory necrolytic erythema). These tumors have a very high malignant potential and are the third most common functional PNET. They are rarely associated with genetic syndromes, in contrast to some other PNETs.
Diagnosis
Indications for Testing
- Pancreatic tumor
- Clinical symptoms of glucose intolerance, hyperglycemia, weight loss and cachexia, and migratory necrotic erythema rash
Laboratory Testing
- Serum glucose – elevated
- Glucagon (fasting)
- Elevated concentration suggestive of glucagonoma
- Chromogranin A (Kunz, North American Neuroendocrine Tumor Society [NANETS], 2013)
- Can be used as a marker of disease activity and for posttreatment surveillance
Histology
Diagnosis made by morphology and immunochemical testing
Imaging Studies
- Multiphasic contrast enhanced computed tomography (CT) or magnetic resonance imaging (MRI)
- If negative, proceed to scintography for tumor identification
- Somatostatin-receptor scintigraphy (Indium-111 OctreoScan) may help localize small lesions
Differential Diagnosis
- Skin rash
- Necrolytic migratory erythema in association with cirrhosis, pancreatitis, or celiac disease
- Psoriasis
- Paraneoplastic syndromes
- Vitamin/mineral deficiency syndromes (eg, pellagra, zinc)
- Toxic epidermal necrolysis associated with other disorders (eg, hepatitis B)
- Immunobullous disease
- Herpes simplex virus
- Seborrheic/contact dermatitis
- Hyperglycemia
- Diabetes mellitus (type 1 or type 2)
- Metabolic syndrome
- Deep vein thrombosis
- Thrombophilia
- Antiphospholipid syndrome
- Malignancy
- Other malignancy
- Pancreatic adenocarcinoma
Monitoring
- Chromogranin A (Kunz, NANETS, 2013)
- Recommended for patients with advanced disease who had elevated levels at diagnosis
- Consider for patients with resected disease
Background
Epidemiology
- Incidence – <1/million (Falconi, European Neuroendocrine Tumor Society [ENETS] consensus, 2016)
- Age – 50s-60s (median)
- Sex – M:F, equal
Familial Genetics
Rarely associated with genetic variations; however, patients diagnosed with multiple endocrine neoplasia 1 (MEN1), von Hippel-Lindau, neurofibromatosis type 1 (NF1), or tuberous sclerosis are at higher risk for PNETs (Falconi, ENETS, 2016)
Pathophysiology
- Usually sporadic
- Tumor is usually large (5-10 cm) when discovered
- Typically, a single tumor is found
- Tumor size >5 cm associated with malignancy in 60-80% of cases
- ~15% of functional PNETs
- Tumor of alpha cells of pancreatic islets – small number in proximal duodenum
- Most frequently malignant (50-80%) (Falconi, ENETS, 2016), calcified, and located in body and tail of pancreas with regional node involvement
- Secretes excessive amounts of glucagon – stimulates glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, and insulin secretion
Clinical Presentation
- Laboratory – hyperglycemia, panhypoaminoaciduria
- Glossitis, stomatitis, angular cheilitis
- 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 and cachexia
- Frequently metastatic at presentation
- Liver is most common site of metastasis, followed by lymph nodes or bone
ARUP Laboratory Tests
Use to diagnose and manage diabetes mellitus and other carbohydrate metabolism disorders
Quantitative Enzymatic Assay
Aid in diagnosis and monitoring of glucagonoma
Quantitative Radioimmunoassay
Aid in monitoring
Not recommended for diagnosis of carcinoid tumors
May be useful in monitoring nonsecretory sympathetic and parasympathetic neuroendocrine tumors
Immunofluorescence
Aid in histologic diagnosis of pancreatic neuroendocrine tumors (PNETs)
Stained and returned to client pathologist; consultation available if needed
Immunohistochemistry
Aid in histologic diagnosis of PNETs
Stained and resulted by ARUP
Immunohistochemistry
Aid in histologic diagnosis of PNETs
Stained and returned to client pathologist; consultation available if needed
Immunohistochemistry
Aid in histologic diagnosis of PNETs
Stained and returned to client pathologist; consultation available if needed
Immunohistochemistry
References
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Cruz-Bautista I, Lerman I, Perez-Enriquez B, et al. Diagnostic challenge of glucagonoma: case report and literature review. Endocr Pract. 2006;12(4):422-426.
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Falconi M, Eriksson B, Kaltsas G, et al. ENETS Consensus Guidelines Update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103(2):153-171.
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Jabbour SA, Davidovici BB, Wolf R. Rare syndromes. Clin Dermatol. 2006;24(4):299-316.
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Jensen RT, Cadiot G, Brandi ML, et al. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology. 2012;95(2):98-119.
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Kunz PL, Reidy-Lagunes D, Anthony LB, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013;42(4):557-577.
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NCCN - Neuroendocrine Tumors
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and adrenal tumors. Version 4.2018. [Updated: May 2018; Accessed: Jul 2018]
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Oberg K. Pancreatic endocrine tumors. Semin Oncol. 2010;37(6):594-618.
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Oberg K, Knigge U, Kwekkeboom D, et al. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(Suppl 7):vii124-130.
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Perren A, Couvelard A, Scoazec JY, et al. ENETS Consensus Guidelines for the standards of care in neuroendocrine tumors: pathology: diagnosis and prognostic stratification. Neuroendocrinology. 2017;105(3):196-200.
CAP - Pancreas (Endocrine)
College of American Pathologists (CAP). Protocol for the examination of specimens from patients with tumors of the endocrine pancreas. Version 3.3.0.1. [Posted: Aug 2016; Accessed: Mar 2020]
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Vinik AI, Woltering EA, Warner RR , et al. NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas. 2010;39(6):713-734.
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