Glucagonomas are neuroendocrine tumors of the pancreatic islets that secrete glucagon. Glucagonoma syndrome occurs due to the effects of elevated glucagon levels secreted by the tumor. The first case was described in 1942 by Becker et al. in a 45-year-old woman presenting with widespread dermatitis, weight loss, glossitis, and abnormal glucose tolerance associated with an islet cell neoplasm of the pancreas on autopsy specimen. IN 1966, McGavran and colleagues identified the classic symptoms of mild diabetes and dermatitis along with elevated glucagon levels related to a metastatic alpha cell tumor of the pancreatic islets. This review highlights the clinical presentation and management of glucagonomas.
Glucagonomas are neuroendocrine tumors originating from multipotential stem cells of endodermal origin. They arise from the alpha cells of the islets in the pancreas. Most glucagonomas are solitary. However, less than 10% of them have been associated with multiple endocrine neoplasia 1 syndrome (MEN1).
Glucagonomas are sporadic and rare. The annual occurrence is 0.01 to 0.1 new cases per 100,000. They are typically large (greater than 3 cm) and located mainly in the tail or the body of the pancreas due to the high prevalence of alpha cells in this area. Over 50% are metastatic at the time of diagnosis. The incidence of glucagonoma in males and females is similar. Most patients with glucagonoma present in the fifth to sixth decade of life.
Glucagon is a single-chain polypeptide made up of 29 amino acids that are derived from a larger precursor peptide, which is cleaved upon secretion. The main site of glucagon production is pancreatic alpha-islet cells, which secrete glucagon in response to hypoglycemia, amino acids, gastric inhibitory peptide, and ghrelin. Glucagon acts in the liver to increase glycogenolysis and gluconeogenesis by stimulating the cAMP pathway resulting in an elevation of plasma glucose. The secretion of glucagon is inhibited by hyperglycemia, insulin, somatostatin, and GLP-1. It also causes relaxation of the smooth muscle of the stomach, duodenum, small bowel, and colon. The other actions of glucagon include stimulation of lipolysis.
Excessive secretion of glucagon from the tumor leads to the glucagonoma syndrome. Classic glucagonoma syndrome consists of weight loss, necrolytic migratory erythema (NME), diabetes, and mucosal abnormalities including stomatitis, cheilitis, and glossitis. The precise etiology of NME is not known, but it is thought secondary to a combination of poor nutrition, low zinc, and amino acid levels. Diabetes results secondary to the direct effects of glucagon. Diarrhea may occur from increased glucagon levels and co-secretion of gastrin, VIP, serotonin, or calcitonin.
Glucagonoma syndrome also goes by the acronym 4D syndrome, consisting of dermatosis, diabetes, deep vein thrombosis, and depression.
Glucagonoma should be suspected in patients with NME associated with or without the other symptoms discussed above.
Tumor localization is typically started with a helical multiphasic contrast-enhanced CT scan. The sensitivity of multiphasic CT scans is significantly high at greater than 80% for detecting intrapancreatic neuroendocrine tumors.
MRI is performed in case of indeterminate lesions and may have a better sensitivity to detect liver metastases.
Glucagonomas express abundant somatostatin receptors as compared to other pancreatic neuroendocrine tumors. Hence, they are suitable for localization using somatostatin analogues like octreotide. Somatostatin receptor scintigraphy (SRS) was positive in 97% of glucagonoma patients, as noted in a study by Kindmark et al.. It also has the advantage of detecting small, occult metastases within and outside of the abdomen and hence, helpful in the staging of the tumor.
Functional PET imaging technique with DOTA peptides like DOTATATE, DOTANOC, DOTATOC could be used in the localization of non-metastatic tumors. They offer higher spatial resolution as compared to the SRS and provide higher sensitivity, particularly in the detection of smaller lesions.
Management of progressive/Metastatic Disease
The most common site of metastasis is liver. Hepatic resection has been recommended in patients without widespread liver involvement, diffuse extrahepatic metastases, and decreased liver function. Resection has led to a decrease in glucagon levels and significant improvement of NME.
Hepatic arterial embolization with or without selective hepatic artery infusion of chemotherapy is a palliative method used in patients with symptomatic hepatic metastases and are not candidates for hepatic resection.
Radiofrequency ablation applies to smaller lesions (typically smaller than 3 cm) and is less invasive than hepatic resection or hepatic arterial embolization. It can be used as in conjunction with surgical resection, or as a primary treatment technique for the hepatic metastases.
Combination chemotherapy with streptozocin, 5-fluorouracil or Temozolomide containing regimens, often in combination with a somatostatin analog have been used in patients with large tumors and enlarging metastases. The use of systemic chemotherapy is limited to patients with advanced disease.
Molecular targeted agents such as sunitinib, a tyrosine kinase inhibitor, and everolimus, a mTOR inhibitor are approved in the United States for treatment of advanced, well-differentiated, pancreatic neuroendocrine tumors including glucagonomas,.
Peptide receptor radionuclide therapy (PRRT), also known as radioisotope therapy, is a novel method being used for the management of neuroendocrine tumors. The high expression of somatostatin receptors in glucagonoma provides an opportunity for the use of PRRT.
Glucagonomas are typically slow growing; however, they are usually advanced by the time of diagnosis. The predictors of survival are dependent on age, tumor grade, and distant metastases. The cure is rarely achieved once the tumor is metastatic.
As per the National Comprehensive Cancer Network guidelines, the post-resection follow up includes history and physical examination, serum glucagon level, CT or MRI in the initial 3 to 12-month period. After 1 year, it is recommended to follow the same measures every 6 to 12 months up to a maximum of 10 years.
Glucagonoma syndrome is difficult to diagnose and once diagnosed a challenge to manage. An interprofessional team of nurses, primary care providers, and specialists must work together to monitor the patient as they are at risk for developing dermatosis, diabetes, deep vein thrombosis, and depression. [Level V]
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