Glucagonoma pathophysiology

	Glucagonoma Microchapters
Home
Patient Information
Overview
Historical Perspective
Pathophysiology
Causes
Differentiating Glucagonoma from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Staging
History and Symptoms
Physical Examination
Laboratory Findings
Chest X Ray
CT
MRI
Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Glucagonoma pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Glucagonoma pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Glucagonoma pathophysiology
CDC on Glucagonoma pathophysiology
Glucagonoma pathophysiology in the news
Blogs on Glucagonoma pathophysiology
Directions to Hospitals Treating Glucagonoma
Risk calculators and risk factors for Glucagonoma pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

Overview

Pathogenesis

A glucagonoma is a rare tumor of the alpha cells of the pancreas that results in the overproduction of the hormone glucagon.
It causes hyperglucagonemia, zinc deficiency, fatty acid deficiency, hypoaminoacidemia that may cause necrolytic migratory erythema.
The postulated mechanism for necrolytic migratory erythema involves excessive inflammation in the epidermis in response to trauma and to the necrolysis.^[1]^[2]
Glucagon increases gluconeogenesis from amino acid substrates. This causes weight loss due to the catabolic action of glucagon.^[3]
Necrolytic migratory erythema probably results from hyponutrition and amino acid deficiency.^[4]
Diarrhea may result from the secretion of gastrin occurs with hyperglucagonoma.

Genetics

Glucagonoma may be part of multiple endocrine neoplasia type1 (MEN1). It is an autosomal dominant syndrome that is usually caused by mutations in the MEN1 gene.

It is characterized by the development of the following tumors:^[1]
Pituitary adenomas
Islet cell tumors of the pancreas (commonly gastrinoma and glucagonoma)
Parathyroid hyperplasia with resulting hyperparathyroidism
The gene locus causing multiple endocrine neoplasia type 1 has been localized to chromosome 11q13 by studies of loss of heterozygosity on multiple endocrine neoplasia type 1-associated tumors and by linkage analysis in multiple endocrine neoplasia type 1 families.^{[2][3][4][5][6]}MEN1, spans about 10 Kb and consists of ten exons encoding a 610 amino acid nuclear protein, named menin.^[2]
MEN1 gene is a putative tumor suppressor gene and causes type 1 multiple endocrine neoplasia by Knudson's "two hits" model for tumor development.^[7]
two hits model for tumor development suggests that there is a germline mutation present in all cells at birth and the second mutation is a somatic mutation that occurs in the predisposed endocrine cell and leads to loss of the remaining wild type allele. This "two hits" model gives cells the survival advantage needed for tumor development.

Gross Pathology

Glucagonomas are neuroendocrine tumors derived from multipotential stem cells.

Glucagonomas are generally large tumors at diagnosis with a mean diameter of 5 cm, From 50 to 82% have evidence of metastatic spread at presentation.

Nearly all glucagonomas are located in the pancreas, 50–80% occur in the pancreatic tail, 32.2% in the body and 21.9% in the head.
In few patients, the location was extrapancreatic, such as in kidney, duodenum, lung, accessory pancreatic tissue.

Metastasis usually occurs to the liver. The most common site for distal metastases is the liver.
Other sites are lymph nodes, bone, mesentery, lung, and adrenals.^[5]

Tumors below 2 cm in diameter are associated with a very low chance of malignancy.

Microscopic Pathology

Many glucagonomas are pleomorphic^[6] with cells containing granules that stain for other peptides, most frequently pancreatic polypeptide.^[7]
Glucagon is usually detectable within the tumor cells by immunoperoxidase staining, and glucagon mRNA may be detected.
Electron microscopy reveals a variable number of secretory granules, indicative of their alpha cell origin.
Benign tumors are usually fully granulated, whereas malignant cells have fewer granules.^[8]

Images

Confluent epidermal necrosis (high mag)^[9]
Confluent epidermal necrosis (very high mag)^[9]
Confluent epidermal necrosis (intermed mag)^[9]
Confluent epidermal necrosis (low mag)^[9]
(A) Skin lesions affecting pretibial area. (B) Skin biopsy in necrolytic migratory erythema showing a zone of necrolysis and vacuolated keratinocytes^[10]
Skin biopsy in necrolytic migratory erythema showing a large zone of necrolysis in the upper epidermis (arrow)^[11]
A) Psoriasiform hyperplasia of the epidermis with overlying parakeratosis and mild perivascular infiltrate of lymphocytes in the upper dermis (HE 5 X). B) Vascular dilatation (HE 20 X).^[12]
Specimen from distal splenopancreatectomy.A) The neoplasia is located in the inferior border of the pancreas (arrow); it shows an exophytic growth but appears well circumscribed. B) The cut surface is whitish-yellow in color with focal areas of hemorrhage.^[12]
Histopathological examination of the pancreatic tumor.A) The tumor appears encapsulated and composed of polygonal cells with trabecular or ribbon-like proliferation (HE 5 X). B) At immunohistochemistry, neoplastic cells showed an intense diffuse staining for glucagon (Anti-glucagon antibody 5 X)^[12]