Glucagonoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2] Mohammed Abdelwahed M.D [3]

Overview

Glucagonoma is a rare tumor of the alpha cells of the pancreas that results in the overproduction of the hormone glucagon. Glucagonoma causes hyperglucagonemia, zinc deficiency, fatty acid deficiency, hypoaminoacidemia that may cause necrolytic migratory erythema. Glucagonoma may be a part of multiple endocrine neoplasia type1 (MEN1). It is an autosomal dominant syndrome that is usually caused by mutations in the MEN1 gene. MEN1 gene is a tumor suppressor gene and causes type 1 multiple endocrine neoplasia by Knudson's "two hits" model for tumor development. 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. Glucagonoma can metastasize mainly to the liver. Glucagonomas consist of pleomorphic cells containing granules that stain for other peptides, most frequently pancreatic polypeptide. Immunoperoxidase staining can detect glucagon within the tumor cells and glucagon.

Pathogenesis

Glucagonoma is a rare tumor of the alpha cells of the pancreas that results in the overproduction of the hormone glucagon. Glucagonomas are neuroendocrine tumors derived from multipotential stem cells.^[1]
Glucagon increases glycogenolysis, gluconeogenesis from amino acid substrates and inhibits glycolysis. This causes weight loss due to the catabolic action of glucagon.^[2]
When glucagon is secreted by a tumor, it becomes independent and is no longer influenced by feedback control mechanisms.
Glucagonoma causes hyperglucagonemia, zinc deficiency, fatty acid deficiency, hypoaminoacidemia that may cause necrolytic migratory erythema.
The mechanism for necrolytic migratory erythema involves excessive inflammation in the epidermis in response to trauma and to the necrolysis.^[3]^[4]
Necrolytic migratory erythema (NME) probably results from hyponutrition and amino acid deficiency. It can be caused by the loss of tryptophan in cutaneous tissues as a result of the excess circulating glucagon. Tryptophan is responsible for niacin function, which regulates cell turnover and the maturation of the epidermis and mucosal epithelia.^[5]^[6]
Diarrhea may result from the secretion of gastrin occurs with glucagonoma.

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]^{[2][3][4][5][6]}^[7]
- 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.MEN1, spans about 10 Kb and consists of ten exons encoding a 610 amino acid nuclear protein, named menin.
MEN1 gene is a tumor suppressor gene and causes type 1 multiple endocrine neoplasia by Knudson's "two hits" model for tumor development.
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

The gross pathology of glucagonoma may show:^[7]^[8]^[9]

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. Other sites are lymph nodes, bone, lung, and adrenals.

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

Microscopic Pathology

The microscopic pathology of glucagonoma tumors in pancreas usually show intense staining for glucagon.^[10]^[11]

Many glucagonomas are pleomorphic with cells containing granules that stain for other peptides, most frequently pancreatic polypeptide.
Immunoperoxidase staining can detect glucagon within the tumor cells and glucagon mRNA also may be detected.
Electron microscopy shows secretory granules indicating the origin of glucagonoma from alpha cells.
Benign tumors are usually fully granulated and malignant cells have fewer granules.
Skin biopsy may show epidermal necrosis.

Images

Histology of confluent epidermal necrosis (high mag),Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054^[12]
Histology of confluent epidermal necrosis (very high mag)Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054^[12]
Histology of confluent epidermal necrosis (intermed mag)Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054^[12]
Histology of confluent epidermal necrosis (low mag)Source:By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054^[12]
(A) Skin lesions affecting pretibial area. (B) Skin biopsy in necrolytic migratory erythema showing a zone of necrolysis and vacuolated keratinocytes^[7]
Skin biopsy in necrolytic migratory erythema showing a large zone of necrolysis in the upper epidermis (arrow)^[9]
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).^[13]
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.^[13]
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)^[13]