Glucagonoma Syndrome

Etiology

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)[3].

Epidemiology

Glucagonomas are sporadic and rare. The annual occurrence is 0.01 to 0.1 new cases per 100,000[4]. 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.

Pathophysiology

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[5]. 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[6]. 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.

History and Physical

Glucagonoma syndrome also goes by the acronym 4D syndrome, consisting of dermatosis, diabetes, deep vein thrombosis, and depression[7].

• The dermatoses associated with glucagonoma syndrome is called necrolytic migratory erythema (NME). It was first described by Wilkinson[8]. It is present in up to 90% of the patients. It is widespread, with main areas of involvement being perioral, perigenital regions and the extremities. NME often starts as pruritic and painful erythematic papules or plaques which gradually enlarge and coalesce to form bullous lesions. Mucosal involvement presents in the form of angular cheilitis, glossitis, stomatitis, and blepharitis[9]. Patients may also have hair loss and nail dystrophy.
• Weight loss occurs in about 90% of the patients with glucagonoma syndrome and is also one of the presenting features.
• Diabetes mellitus is present in nearly 80% of the patients. It is mostly mild as beta cell function of the pancreas is preserved and hence the production of insulin-mitigating ketoacidosis.
• Deep vein thrombosis is noted in nearly 50% of the patients. Patients with the unexplained thromboembolic disease should undergo a thorough history, physical and evaluation for the possibility of glucagonoma. It can occasionally present as pulmonary embolism which can be fatal.
• Depression, occurring in about 50% of the patients, may be related to the chronic dermatosis. Other neuropsychiatric manifestations include dementia, psychosis, agitation, hyperreflexia, ataxia, paranoid delusions, and proximal muscle weakness.
• Chronic diarrhea is seen in about 30% of the patients with glucagonoma syndrome.

Evaluation

Glucagonoma should be suspected in patients with NME associated with or without the other symptoms discussed above.

• A fasting plasma glucagon level should be drawn. Fasting plasma glucagon levels are abnormally elevated usually greater than 500 pg/mL. Normal fasting plasma glucagon levels are less than 150 pg/mL. It is important to note that different glucagon assays may exhibit variable cross-reactivity with different isoforms of glucagon, not all of which (nearly 70%) are biologically active. Serial measurements should, therefore, always be performed using the same assay directed against the C-terminus.
• Serum concentrations of amino acids and zinc should be checked to evaluate the nutritional status. The laboratory abnormalities with glucagonoma can include hypoaminoacidemia (due to targeting of amino acids into metabolic pathways in the liver by excessive hyperglucagonemia) and low zinc levels.
• A complete blood count (CBC) should be obtained to check for concurrent normocytic anemia. A comprehensive metabolic panel (CMP) should be checked to detect other metabolic abnormalities.
• Obtaining serum parathyroid hormone, gastrin, insulin, pancreatic polypeptide, serotonin, vasoactive intestinal polypeptide (VIP), prolactin and ACTH levels is important as glucagonoma can rarely be associated with the MEN1 syndrome.
• Skin biopsy of the NME lesion shows small bullae consisting of acantholytic epidermal cells along with lymphocytic and neutrophilic infiltrate. The dermis contains a perivascular lymphocytic infiltrate with an intact epidermis.

Imaging Studies

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.[10]. 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.

Treatment / Management

Initial Management

• Surgical resection is the only curative option in a minority of cases where the tumor is localized at the time of diagnosis[11]. The type of pancreatic resection is determined after careful assessment of the site and size of the tumor.
• Nutritional support includes total parenteral nutrition, supplementation of amino acids and zinc supplementation to reverse the effects of malnutrition and catabolic effects of weight loss from the glucagon.
• Antibiotics, zinc replacement, and steroids may help with the improvement of NME. 
• Somatostatin analogs like octreotide and lanreotide help to reverse the effects of glucagon excess as well as inhibit secretion of glucagon [12]. Octreotide LAR and Lanreotide have been reported to significantly lengthen the time to tumor progression[13],[14]. It also improves NME, diabetes, diarrhea, and neurological symptoms.
• Prophylactic anticoagulant therapy, for example, heparin to prevent deep venous thrombosis is mandatory for all patients during the perioperative period.
(A1)

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[15]. Resection has led to a decrease in glucagon levels and significant improvement of NME.(B2)

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[16].

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[17].

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[18].(B3)

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[19],[20].(A1)

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[21].

Differential Diagnosis

• Fasting plasma glucagon levels may be elevated in other conditions like acute trauma, diabetes mellitus, burn injury, sepsis, renal failure,  cirrhosis, pancreatitis or Cushing syndrome. Though the fasting plasma glucagon levels in these conditions are elevated, it is typically less than 500 pg/mL. A rare disorder due to an inactivation mutations defect in the glucagon receptor gene that causes pancreatic alpha cell hyperplasia, an elevation of glucagon without symptoms is called Mahvash disease[22].
• NME is not specific to glucagonoma and can also be seen in with chronic liver disease, inflammatory bowel disease, pancreatitis, heroin abuse, jejunal and rectal adenocarcinoma, and myelodysplastic syndrome.
• NME-like lesions have been associated with essential fatty acid deficiency, zinc deficiency (acrodermatitis enteropathica), and the dermatosis of protein-calorie malnutrition.

Prognosis

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.