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]

Overview

A glucagonoma is a rare tumor of the alpha cells of the pancreas that results in the overproduction of the hormone glucagon. On microscopic histopathological analysis, findings of glucagonoma are epidermal necrosis, subcorneal pustules, confluent parakeratosis, epidermal hyperplasia and marked papillary dermal angioplasia, and suppurative folliculitis.

Pathogenesis

All cases of the glucagonoma have been associated with tumors originating in the alpha cells of the pancreas. Glucagon, acting on the liver, increases both amino acid oxidation and gluconeogenesis from amino acid substrates [6]. The weight loss characteristic of glucagonoma may result from the catabolic action of glucagon and through glucagon-like peptides such as GLP-1. Necrolytic migratory erythema probably results from hyponutrition and amino acid deficiency [7]. Diarrhea may result from hyperglucagonemia and co-secretion of gastrin, vasoactive intestinal peptide, serotonin, or calcitonin [2].

Pathogenesis of necrolytic migratory erythema is ill defined. The postulated mechanism for necrolytic migratory erythema involves the combined effect of hyperglucagonemia, zinc deficiency, fatty acid deficiency, hypoaminoacidemia, and liver disease, that lead to excessive inflammation in the epidermis in response to trauma and to the necrolysis.^[1]^[2]

Genetics

Mahvah disease is due to a homozygous P86S mutation of the human glucagon receptor. It is associated with the development of α-cell hyperplasia, hyperglucagonemia, and the development of nonfunctioning pNETs. A second

disease called glucagon cell adenomatosis can mimic glucagonoma

syndrome clinically and is characterized by the presence of hyperplastic

islets staining positive for glucagon instead of a single glucagonoma.

Associated Conditions

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. 22

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

Microscopic Pathology

Many glucagonomas are pleomorphic36,37 with cells containing granules that stain for other peptides, most frequently pancreatic polypeptide. 36,38
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. 35,39

Images

Confluent epidermal necrosis (high mag)^[3]
Confluent epidermal necrosis (very high mag)^[3]
Confluent epidermal necrosis (intermed mag)^[3]
Confluent epidermal necrosis (low mag)^[3]
(A) Skin lesions affecting pretibial area. (B) Skin biopsy in necrolytic migratory erythema showing a zone of necrolysis and vacuolated keratinocytes^[4]
Skin biopsy in necrolytic migratory erythema showing a large zone of necrolysis in the upper epidermis (arrow)^[5]
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).^[6]
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.^[6]
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)^[6]