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Glucagonoma and the glucagonoma syndrome

Glucagonoma and the glucagonoma syndrome
Author:
Emily Bergsland, MD
Section Editors:
David M Nathan, MD
David C Whitcomb, MD, PhD
Deputy Editor:
Shilpa Grover, MD, MPH, AGAF
Literature review current through: Jan 2024.
This topic last updated: Mar 15, 2023.

INTRODUCTION — Glucagonomas are rare functioning neuroendocrine tumors that secrete glucagon. This topic will review the clinical manifestations, diagnosis, and management of glucagonomas. An overview of the clinical manifestations, diagnosis, and management of pancreatic neuroendocrine tumors and other functioning pancreatic neuroendocrine tumors are discussed in detail, separately. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms" and "Surgical resection of sporadic pancreatic neuroendocrine tumors" and "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion" and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion" and "Insulinoma" and "Somatostatinoma: Clinical manifestations, diagnosis, and management" and "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis" and "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)".)

EPIDEMIOLOGY — Glucagonomas are rare, with an annual incidence of 0.01 to 0.1 new cases per 1,000,000 [1]. Glucagonomas are usually solitary, and the majority are located in the distal pancreas. Patients typically present in their fifth decade [2]. While most glucagonomas are sporadic, up to 20 percent may be associated with the multiple endocrine neoplasia syndrome type 1 (MEN1). However, glucagonomas occur in only 3 percent of MEN1 patients [3]. Glucagonomas are usually large (>3 cm), and approximately 50 to 80 percent are metastatic at diagnosis. Unlike tumors complicated by carcinoid syndrome, however, liver metastases are not typically a prerequisite for the clinical syndrome. (See "Clinical features of carcinoid syndrome" and "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

CLASSIFICATION, NOMENCLATURE, AND HISTOLOGY — Glucagonomas are neuroendocrine tumors (NETs) derived from multipotential stem cells of endodermal origin. The World Health Organization classifies NETs arising within the digestive system based upon the extent to which they resemble their normal non-neoplastic counterparts (table 1). (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on '2010 and 2019 World Health Organization classification'.)

Nearly all reported cases of the glucagonoma syndrome have been associated with tumors originating in the alpha cells of the pancreas [2,4]. Histologically, the tumors consist of cords and nests of well-differentiated NETs with few mitoses and a histologic appearance that is similar to that of other pancreatic NETs. The cells are arranged in a solid, trabecular, gyriform, or glandular pattern, with fairly uniform nuclei, salt-and-pepper chromatin, and finely granular cytoplasm. Glucagon is usually detectable within the tumor cells by immunoperoxidase staining, and glucagon mRNA may be detected by in situ hybridization. Characteristic alpha cell granules may be seen on electron microscopy.

PATHOPHYSIOLOGY — Glucagonoma syndrome is thought to be directly related to elevated glucagon levels. Glucagon, acting on the liver, increases both amino acid oxidation and gluconeogenesis from amino acid substrates [5]. 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 [6]. Diarrhea may result from hyperglucagonemia and co-secretion of gastrin, vasoactive intestinal peptide, serotonin, or calcitonin [2].

CLINICAL FEATURES — As the clinical features of glucagonoma syndrome are non-specific, many patients are diagnosed late when the disease has metastasized [7]. (See 'Epidemiology' above.)

Weight loss — Weight loss, often significant, is the most common presenting feature, occurring in 60 to 80 percent of patients with glucagonoma syndrome [2,7].

Necrolytic migratory erythema — Necrolytic migratory erythema (NME) is the presenting feature of glucagonoma syndrome in approximately 70 to 80 percent of patients [2,7-9]. Although the rash can occasionally be the only symptom, in most cases patients have associated systemic symptoms. NME characteristically begins as erythematous papules or plaques involving the face, perineum, and extremities (picture 1) [10]. Over the ensuing 7 to 14 days, the lesions enlarge and coalesce. Central clearing then occurs, leaving bronze-colored, indurated areas centrally, with blistering, crusting, and scaling at the borders. The affected areas are often pruritic and painful. The same process often affects the mucous membranes, resulting in glossitis, angular cheilitis, stomatitis, and blepharitis. Patients with NME often have associated hair loss and nail dystrophy.

The diagnosis of NME is made with skin biopsies obtained from the edge of the lesions, which reveal superficial necrolysis with separation of the outer layers of the epidermis and perivascular infiltration with lymphocytes and histiocytes. However, multiple biopsies are often required to demonstrate these findings. NME is not specific for glucagonoma syndrome and has been reported in association with other disorders in the absence of elevated glucagon levels [11,12]. (See 'Differential diagnosis' below.)

Glucose intolerance/diabetes mellitus — Glucose intolerance occurs in 68 to 95 percent of patients with glucagonoma [2,7,13]. However, clinically significant hyperglycemia with diabetes mellitus is only present at diagnosis in approximately 40 percent of patients. Hyperglycemia due to glucagonoma syndrome does not usually result in diabetic ketoacidosis, since beta cell function is preserved and insulin secretion is normal [2].

Other

●Chronic diarrhea is the most frequent gastrointestinal manifestation of glucagonoma syndrome and is present in approximately 14 to 18 percent of patients with glucagonoma syndrome [14].

●Venous thrombosis occurs in up to 50 percent of patients with glucagonoma and usually manifests as deep vein thrombosis or pulmonary embolism [13,15]. Unexplained thromboembolic disease in a patient with a neuroendocrine tumor should alert one to the possibility of glucagonoma.

●Neuropsychiatric manifestations occur in 20 percent of patients with glucagonoma. Manifestations include depression, insomnia, dementia, psychosis, agitation, paranoid delusions, ataxia, hyperreflexia, optic atrophy, and proximal muscle weakness [7,16].

●Dilated cardiomyopathy has been reported in patients with glucagonoma syndrome [7,17,18].

●Glossitis, stomatitis, or cheilitis has been reported in 41 percent of patients [7].

Laboratory abnormalities — In addition to elevated serum glucagon levels and hyperglycemia, glucagonoma syndrome has been associated with other non-specific laboratory abnormalities. A normocytic normochromic anemia is present in up to 90 percent of patients [7]. Anemia may be due to anemia of chronic disease or a direct effect of glucagon on erythropoiesis [4]. Amino acid levels are markedly diminished. Patients with glucagonoma may also have minor elevations of secondary hormones, including gastrin, somatostatin, vasoactive intestinal peptide, serotonin, adrenocorticotrophic hormone, and pancreatic polypeptide [2]. (See 'Serum glucagon' below and 'Glucose intolerance/diabetes mellitus' above.)

DIAGNOSIS — Glucagonoma syndrome should be suspected in patients with necrolytic migratory erythema with or without associated weight loss, glucose intolerance, chronic diarrhea, or venous thrombosis. The diagnosis of glucagonoma is established with an inappropriately elevated fasting plasma glucagon level.

Serum glucagon — The diagnosis of a glucagonoma requires the demonstration of increased plasma glucagon levels (>500 pg/mL) [2]. Plasma glucagon levels are usually elevated 10- to 20-fold in patients with glucagonoma (normal <50 pg/mL). Concentrations above 1000 pg/mL are virtually diagnostic of glucagonoma. However, up to 70 percent of the immunoreactive glucagon may be biologically inactive [19]. A blood glucose should be tested concurrently. Histologic diagnosis by biopsy is not required to make the diagnosis.

Conditions other than glucagonoma that can induce moderate elevations in the serum glucagon concentration (<500 pg/mL) include hypoglycemia, fasting, trauma, sepsis, acute pancreatitis, abdominal surgery, Cushing's syndrome, and renal and hepatic failure [2]. Idiopathic hyperglucagonemia syndrome, either familial or sporadic, is associated with a large molecular weight form of the peptide. In addition, other neuroendocrine tumors, such as carcinoid tumors, insulinomas, and gastrinomas, can secrete glucagon, although rarely in high enough levels to cause the classic clinical syndrome [20,21].

However, some glucagonomas are associated with serum levels of the peptide in the "physiologically elevated" range, even in the presence of necrolytic migratory erythema. Thus, in patients with the classic syndrome, a serum glucagon concentration below 500 pg/mL does not exclude a glucagonoma [7,19].

GENETICS — Most glucagonomas are sporadic, but up to 10 percent occur in the setting of the Multiple Endocrine Neoplasia-Type I (MEN-1) hereditary cancer syndrome [3]. Of note, a small subset of patients appearing to have MEN-1 do not harbor mutations in the MEN-1 gene, but have a mutation in a cyclin dependent kinase inhibitor (CDK) gene such as, CDK1B [22]. In addition, data suggest that 17 percent of patients with seemingly sporadic panNETs harbor germline alterations in any one of a variety of genes (including MUTYH, CHEK2, and BRCA2, as well as MEN-1 and VHL), suggesting that all patients with glucagonoma should at least be considered for testing for inherited genetic syndromes [23]. At a minimum, patients should be evaluated for a personal or family history consistent with MEN-1 or other inherited syndrome.

DIFFERENTIAL DIAGNOSIS — Necrolytic migratory erythema (NME) is not specific for glucagonoma syndrome and has been reported in association with hepatitis B and cirrhosis, jejunal and rectal adenocarcinoma, villous atrophy of the small intestine, and myelodysplastic syndrome in the absence of elevated glucagon levels. (See 'Necrolytic migratory erythema' above.)

NME-like lesions can be seen in a number of other disorders, including zinc deficiency, pellagra, kwashiorkor, end-stage liver disease, toxic epidermal necrolysis, pemphigus foliaceus, and pustular psoriasis. (See "Zinc deficiency and supplementation in children", section on 'Acrodermatitis enteropathica' and "Malnutrition in children in resource-limited settings: Clinical assessment", section on 'Kwashiorkor (edematous malnutrition)' and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Pemphigus foliaceus' and "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

TUMOR LOCALIZATION

Approach to imaging — Imaging studies are required to accurately localize the tumor and stage the extent of disease [24]. Like other neuroendocrine tumors, glucagonomas express somatostatin receptors, thus they are amenable to localization using somatostatin analogs. We begin with helical (spiral) multiphasic contrast-enhanced computed tomography (CT) or contrast-enhanced magnetic resonance imaging (MRI) for evaluation of patients with a glucagonoma. As appropriate, endoscopic ultrasound (EUS), somatostatin-receptor (SSTR) scintigraphy (SRS) or SSTR-positron emission tomography (PET) imaging (preferred) with 68-gallium-DOTA-D-Phe1-Tyr3-octreotate (Gallium Ga-68 DOTATATE), Ga-68 DOTATOC, or 64-Cu-DOTATATE PET/CT should be performed to identify the tumor. Because of its greater sensitivity, SSTR-PET/CT is preferred over conventional SRS with 111-In pentetreotide, where available [25-27]. In addition, we perform Cu-64 DOTATATE, Ga-68 DOTATATE, or GA-68 DOTATOC PET imaging to stage patients at risk for distant spread. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)

●Computed tomography – CT scan is noninvasive and readily available. Intravenous contrast enhances the detection of smaller lesions, especially when images are obtained during the arterial phase. In addition, arterial phase and portal venous phase sequences can be used to maximize the conspicuity of liver metastases compared with the surrounding normal liver parenchyma. CT scans are highly accurate for detecting primary pancreatic neuroendocrine tumors (NETs), and, using multiphase imaging techniques, sensitivity is >80 percent [28-30]. Since most pancreatic glucagonomas are more than 3 cm in size at presentation, a pancreatic mass can usually be identified by CT in the majority of cases [31]. The sensitivity of contrast-enhanced CT for these tumors approaches 100 percent [32,33]. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Computed tomography'.)

●Magnetic resonance imaging – On MRI, pancreatic NETs are typically characterized by low signal intensity on T1-weighted images and high signal intensity on T2-weighted images (image 1 and image 2). MRI may have a higher sensitivity for liver metastases as compared with CT [34]. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Magnetic resonance imaging'.)

●Somatostatin-receptor scintigraphy – SRS (OctreoScan) using radiolabeled form of the somatostatin analog octreotide (Indium-111 [111-In] pentetreotide) has the advantage of instantaneous whole body scanning, which also allows detection of metastases outside of the abdominal region [35]. While SRS can be used for localization and staging of well-differentiated neuroendocrine tumors, it is rapidly being replaced by functional SSTR-PET imaging with G8-Ga-DOTATATE, Ga-68 DOTATOC , or Cu-64 DOTATATE, which have greater spatial resolution and quantification and thus a higher specificity and sensitivity [27,36-38]. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Somatostatin-receptor-based imaging'.)

●Functional SSTR-PET imaging with Ga-68 DOTATATE, Cu-64 DOTATATE, and Ga-68 DOTATOC – Several positron emission tomography (PET) tracers for functional imaging have emerged (18-F-dihydroxy-phenyl-alanine [18F-DOPA], 11-C-5-hydroxytryptophan [11-C-5-HTP], Ga-68-DOTA-D-Phe1-Tyr3-Octreotide [gallium Ga-68-DOTATOC], and Ga-68-DOTA-D-Phe1-Tyr3-Octreotate [galliumGa-68 DOTATATE]) that offer higher spatial resolution than conventional SRS and are associated with improved sensitivity for detection of small lesions [39]. Three of these are approved in the United States for use with PET for localization of somatostatin receptor-positive neuroendocrine tumors (NETs). Integrated PET/CT scanning using Ga-68 DOTATATE, Cu-64 DOTATATE, or Ga-68 DOTATOC is the functional imaging modality of choice for staging and localization of most well differentiated neuroendocrine tumors (where available) [27]. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)

●Endoscopic ultrasound – EUS can detect pancreatic tumors as small as 2 to 3 mm, provide accurate information on the local extent of disease, and allow for transmucosal needle biopsy of pancreatic lesions. However, EUS is rarely used in the evaluation of glucagonomas, as these tumors are diagnosed by hormonal assays and are usually detectable on CT/MRI at diagnosis. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms".)

●Other techniques – Invasive testing to localize the tumor with angiography, laparotomy, or intraoperative ultrasound should be reserved for patients who are strongly suspected of having a glucagonoma in whom imaging is negative [40]. Advances in imaging have nearly eliminated the need for such intervention. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Intraoperative localization techniques'.)

STAGING — Pancreatic endocrine tumors such as glucagonomas are included in the combined American Joint Committee on Cancer/ Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) staging system [41,42]. Five- and ten-year survival rates for patients undergoing resection of pancreatic neuroendocrine tumors (not just glucagonomas) stratified by stage at presentation are presented in the following table (table 2) [43].

In the newest release of the TNM staging classification (8th edition, 2017), the staging systems for endocrine pancreatic tumors (table 3) is separate from that used for exocrine pancreatic tumors [44]. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Staging system'.)

TREATMENT

General measures

●Initial management of patients with glucagonoma syndrome consists of supportive care and management of glucose intolerance/diabetes. Patients with malnutrition may need nutritional support to reverse the catabolic effects of elevated glucagon levels. Parenteral nutrition may be required preoperatively if resection is contemplated. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus" and "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'The perioperative setting'.)

Intermittent infusions of amino and fatty acids have been associated with long-term resolution of necrolytic migratory erythema (NME) [45]. However, the evidence to support their use is limited to observational studies. In addition, amino acid infusions do not cause regression of tumor growth or other symptoms.

●Somatostatin analogs (eg, octreotide, lanreotide) are the treatment of choice to control symptoms related to glucagon hypersecretion [46]. Somatostatin analogs inhibit hormone secretion, reducing serum glucagon concentrations, and improving NME, diabetes, diarrhea, and neurologic symptoms [2,8,14,46-50]. However, the improvement does not always correlate with the fall in serum glucagon, suggesting a direct effect of octreotide on the peripheral target or organ. The dosing and side effects of somatostatin analogues are discussed in detail, separately. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Somatostatin analogs'.)

Pancreatic resection — For the minority of cases in which the tumor is localized at the time of diagnosis, resection of the primary pancreatic tumor is indicated since it offers the chance of complete cure. The type of pancreatic resection (eg, distal pancreatectomy) is dictated by the site and extent of the tumor at the time of laparotomy. Rapid resolution of hyperglucagonemia and NME usually result after resection [51]. However, even in cases deemed to be localized preoperatively, resection results in a cure rate of only about 30 percent [52]. (See "Surgical resection of sporadic pancreatic neuroendocrine tumors" and "Surgical resection of lesions of the body and tail of the pancreas".)

Management of advanced/metastatic disease

Liver-directed therapy

●Surgery – Hepatic resection is indicated for the treatment of metastatic liver disease in the absence of diffuse bilobar involvement, compromised liver function, or extensive extrahepatic metastases (eg, pulmonary, peritoneal). Although the vast majority of cases will not be cured by surgery, resection may increase survival and has the benefit of symptom palliation [53-55]. When feasible, surgical debulking leads to significant reductions in serum glucagon concentration and in the severity of NME, which may resolve completely in some patients [2,56,57]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)

●Hepatic artery embolization – Hepatic arterial embolization with or without selective hepatic artery infusion of chemotherapy is a palliative technique in patients with symptomatic hepatic metastases who are not candidates for surgical resection. Embolization can be performed via the infusion of Gelfoam powder into the hepatic artery through an angiography catheter (bland embolization), or in conjunction with chemotherapy (ie, doxorubicin, cisplatin, or streptozocin, or drug-eluting beads) (chemoembolization). A third embolization technique uses radioactive isotopes (eg, yttrium-90 [90-Y]) that are tagged to glass or resin microspheres and delivered selectively to the tumor via the hepatic artery. Response rates with embolization, as measured by a decrease in hormonal secretion or by radiographic regression, are generally over 50 percent [58-74]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)

●Radiofrequency ablation and cryoablation – Ablation can be used as a primary treatment modality for neuroendocrine liver metastases or as an adjunct to surgical resection [54,55,75]. Ablation can be performed percutaneously or laparoscopically and is less invasive than either hepatic resection or hepatic artery embolization. However, ablation is applicable only to smaller lesions (typically <3 cm), and its long-term efficacy is uncertain. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Ablation'.)

●Liver transplantation – Liver transplantation is considered an investigational approach for metastatic pancreatic neuroendocrine tumors, including glucagonoma, as the number of patients with liver-isolated metastatic disease in whom orthotopic liver transplantation has been attempted is small, and follow-up data are insufficient to judge whether cure has truly been achieved [76-78]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Liver transplantation'.)

Somatostatin analogs — In addition to decreasing hormone secretion and improving symptom control, somatostatin analogs likely have cytostatic activity in this disease extrapolating from studies in other well differentiated neuroendocrine tumors [79,80]. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Somatostatin analogs'.)

Molecularly targeted oral therapy — Molecularly targeted agents (eg, everolimus, sunitinib) have a role in the management of patients with progressive advanced glucagonomas and are discussed elsewhere [81,82] (see "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Molecularly targeted therapy').

Peptide receptor radioligand therapy (PRRT) — A form of peptide receptor radioligand therapy with a radiolabeled somatostatin analog (Lu177 dotatate) is also approved for use in panNETs and has demonstrated efficacy in patients with glucagonoma [83,84]. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Peptide receptor radioligand therapy'.)

Cytotoxic chemotherapy — For patients who are highly symptomatic due to tumor bulk or who have rapidly enlarging metastases, chemotherapy has been used as initial treatment together with a somatostatin analog. The options for therapy typically include a streptozocin-based combination or a temozolomide-containing regimen. However, experience with systemic chemotherapy in patients with glucagonomas, specifically, is limited, and few patients have been included in modern clinical series. The use of cytotoxic chemotherapy in patients with pancreatic neuroendocrine tumors is discussed in detail elsewhere [85-87]. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Cytotoxic chemotherapy'.)

POST-TREATMENT SURVEILLANCE — There is limited evidence from which to make recommendations for follow-up after resection of a glucagonoma. Guidelines from the National Comprehensive Cancer Network, based upon expert consensus, include the following recommendations for follow-up after treatment of a pancreatic neuroendocrine tumor [88]:

●Three to 12 months post-resection: History and physical examination, serum glucagon level, and abdominal multiphasic computed tomography (CT) or magnetic resonance imaging (and chest CT scan +/-contrast as clinically indicated).

●>1 year post-resection to a maximum of 10 years: History and physical examination with serum glucagon level every 6 to 12 months. Abdominal multiphasic computed tomography or magnetic resonance imaging (and chest CT scan +/-contrast) as clinically indicated.

PROGNOSIS — Glucagonomas are generally slow-growing, but are usually advanced by the time of diagnosis. The most common site of metastasis is the liver, followed by regional lymph nodes, bone, adrenal gland, kidney, and lung. Age, grade, and distant metastases are the most significant predictors of survival. Once the tumor is metastatic, cure is rarely, if ever, achieved. However, case series suggest that patients with metastatic disease have a prolonged survival [2,13]. Five- and 10-year survival rates for patients undergoing resection of gastroenteropancreatic neuroendocrine tumors (both pancreatic neuroendocrine and carcinoid tumors) stratified by stage at presentation are presented in the table (table 2).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)

SUMMARY AND RECOMMENDATIONS

●Glucagonomas are rare functioning neuroendocrine tumors that secrete glucagon. They are usually solitary, and the majority are located in the distal pancreas. Approximately 50 to 80 percent are metastatic at diagnosis. (See 'Epidemiology' above.)

●Most glucagonomas are sporadic, but up to 10 percent occur in the setting of the Multiple Endocrine Neoplasia-Type I (MEN-1) hereditary cancer syndrome. At a minimum, patients should be evaluated for a personal or family history consistent with MEN-1 or other inherited syndrome.

●Glucagonoma syndrome is thought to be directly related to elevated glucagon levels. Glucagon, acting on the liver, increases both amino acid oxidation and gluconeogenesis from amino acid substrates. Weight loss results from the catabolic action of glucagon and through glucagon-like peptides such as GLP-1. Necrolytic migratory erythema (NME) probably results from hyponutrition and amino acid deficiency. Hyperglucagonemia and co-secretion of gastrin, vasoactive intestinal peptide, serotonin, or calcitonin lead to diarrhea. (See 'Pathophysiology' above.)

●Glucagonoma syndrome is characterized by NME, cheilitis, glucose intolerance/diabetes mellitus, anemia, weight loss, chronic diarrhea, venous thrombosis, and neuropsychiatric symptoms. Of these, weight loss and NME are the most prevalent symptoms at diagnosis. However, NME is not specific for glucagonoma syndrome and has been reported in association with other disorders. (See 'Clinical features' above.)

●Glucagonoma syndrome should be suspected in patients with NME with or without associated weight loss, glucose intolerance, chronic diarrhea, or venous thrombosis. The diagnosis of glucagonoma is established with an elevated fasting plasma glucagon level (>500 pg/mL). (See 'Diagnosis' above.)

●Imaging studies are required to accurately localize the tumor and stage the extent of disease. We begin with helical (spiral) multiphasic contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). If cross-sectional imaging is inconclusive, endoscopic ultrasound or functional imaging with somatostatin receptor positron emission tomography (SSTR-PET) using Gallium-68-DOTA-0-Phe1-Tyr3-cctreotate (Gallium Ga-68 DOTATATE), Ga-68 DOTA-0-Phe1Tyr3 octreotide (Ga-68 DOTATOC), or Cu-64 DOTATATE should be performed (or somatostatin receptor scintigraphy if SSTR-PET is unavailable) to identify the tumor. In addition, we perform SSTR-PET imaging to fully stage patients at risk for metastatic disease. SSTR-PET imaging with Ga-68 DOTATATE, Ga-68 DOTATOC, or Cu-64 DOTATATE is preferred when available due to its higher specificity and sensitivity (compared with somatostatin receptor scintigraphy). (See 'Approach to imaging' above.)

●Initial management of patients with glucagonoma syndrome consists of supportive care, management of glucose intolerance/diabetes and somatostatin analogs (eg, octreotide) to control symptoms related to glucagon hypersecretion. Patients with malnutrition may need nutritional support to reverse the catabolic effects of elevated glucagon levels. For the minority of cases in which the tumor is localized to the pancreas at the time of diagnosis, resection of the primary pancreatic tumor is indicated.

In patients with metastatic disease, hepatic resection can be considered in the absence of diffuse bilobar involvement, compromised liver function, or extensive extrahepatic metastases. Hepatic arterial embolization with or without selective hepatic artery infusion of chemotherapy may be used for palliation in patients with symptomatic hepatic metastases who are not candidates for surgical resection. Long-term efficacy of radiofrequency ablation and cryoablation are unknown, and experience with orthotopic liver transplantation is limited. Somatostatin analogs are used to delay progression in patients with unresectable disease. In addition, cytotoxic chemotherapy and molecularly targeted agents such as sunitinib and everolimus have activity in well-differentiated panNET. Peptide receptor radioligand therapy with Lu177 dotatate is also an approved option for patients harboring locally advanced or metastatic somatostatin receptor-positive panNETs by functional imaging. (See 'Treatment' above.)

●Glucagonomas are generally slow-growing, but are usually advanced by the time of diagnosis. Once the tumor is metastatic, cure is rarely, if ever, achieved. However, patients with metastatic disease have a prolonged survival. Our approach for follow-up after treatment of a glucagonoma is consistent with guidelines from the National Comprehensive Cancer Network and consists of the following (see 'Prognosis' above):

•3 to 12 months post-resection: History and physical examination, serum glucagon level, and abdominal multiphasic computed tomography or magnetic resonance imaging (and chest CT scan +/-contrast as clinically indicated).

•>1 year post-resection to a maximum of 10 years: History and physical examination with serum glucagon level every 6 to 12 months. Consider abdominal multiphasic computed tomography or magnetic resonance imaging (and chest CT scan +/-contrast) as clinically indicated.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter M. Rosenberg, MD, and Stephen E. Goldfinger, MD, who contributed to an earlier version of this topic review.

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Topic 2611 Version 32.0

References

1 : ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes.

2 : The glucagonoma syndrome. Clinical and pathologic features in 21 patients.

3 : Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: study from the GTE (Groupe des Tumeurs Endocrines) registry.

4 : Glucagonomas and insulinomas.

5 : In vivo assessment of the metabolic alterations in glucagonoma syndrome.

6 : Amino acid deficiency and the skin rash associated with glucagonoma.

7 : Glucagonoma and the glucagonoma syndrome.

8 : Glucagonoma and the glucagonoma syndrome - cumulative experience with an elusive endocrine tumour.

9 : Necrolytic migratory erythema is an important visual cutaneous clue of glucagonoma.

10 : Necrolytic migratory erythema with carcinoma of the pancreas.

11 : Necrolytic migratory erythema without glucagonoma associated with hepatitis B.

12 : Necrolytic migratory erythema with myelodysplastic syndrome without glucagonoma.

13 : The glucagonoma syndrome: clinical features, diagnosis, and treatment.

14 : Perspectives on the current pharmacotherapeutic strategies for management of functional neuroendocrine tumor syndromes.

15 : Perspectives on the current pharmacotherapeutic strategies for management of functional neuroendocrine tumor syndromes.

16 : Neuropsychiatric symptoms, skin disease, and weight loss: necrolytic migratory erythema and a glucagonoma.

17 : Reversible dilated cardiomyopathy associated with glucagonoma.

18 : Glucagonoma-associated dilated cardiomyopathy refractory to somatostatin analogue therapy.

19 : Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years.

20 : Clinical spectrum of hyperglucagonemia associated with malignant neuroendocrine tumors.

21 : Metachronous hormonal syndromes in patients with pancreatic neuroendocrine tumors: a case-series study.

22 : Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states.

23 : Whole-genome landscape of pancreatic neuroendocrine tumours.

24 : ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological, Nuclear Medicine&Hybrid Imaging.

25 : Safety and Efficacy of 68Ga-DOTATATE PET/CT for Diagnosis, Staging, and Treatment Management of Neuroendocrine Tumors.

26 : Prospective Study of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites.

27 : 64Cu-DOTATATE PET/CT for Imaging Patients with Known or Suspected Somatostatin Receptor-Positive Neuroendocrine Tumors: Results of the First U.S. Prospective, Reader-Masked Clinical Trial.

28 : EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors.

29 : Pancreatic tumors: comparison of dual-phase helical CT and endoscopic sonography.

30 : MR imaging of hepatic metastases caused by neuroendocrine tumors: comparing four techniques.

31 : Neuroendocrine tumors: common presentations of uncommon diseases.

32 : Imaging islet cell tumours.

33 : Identification of unknown primary tumors in patients with neuroendocrine liver metastases.

34 : Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors.

35 : VIPomas: an update in diagnosis and management in a series of 11 patients.

36 : Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs).

37 : Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

38 : ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors.

39 : Appropriate Use Criteria for Somatostatin Receptor PET Imaging in Neuroendocrine Tumors.

40 : Glucagonoma diagnosed by arterial stimulation and venous sampling (ASVS).

41 : Glucagonoma diagnosed by arterial stimulation and venous sampling (ASVS).

42 : Prognostic validity of a novel American Joint Committee on Cancer Staging Classification for pancreatic neuroendocrine tumors.

43 : Application of the pancreatic adenocarcinoma staging system to pancreatic neuroendocrine tumors.

44 : Application of the pancreatic adenocarcinoma staging system to pancreatic neuroendocrine tumors.

45 : Peripheral amino acid and fatty acid infusion for the treatment of necrolytic migratory erythema in the glucagonoma syndrome.

46 : Octreotide (SMS 201-995) in the treatment of metastatic glucagonoma: report of one case and review of the literature.

47 : Treatment of inoperable glucagonoma with the long-acting somatostatin analogue SMS 201-995.

48 : Effect of somatostatin on skin lesions and concentrations of plasma amino acids in a patient with glucagonoma-syndrome.

49 : Neuroendocrine tumours of the gut: long-term therapy with the somatostatin analogue SMS 201-995.

50 : Clinical evaluation of SMS 201-995. Long-term treatment in gut neuroendocrine tumours, efficacy of oral administration, and possible use in non-tumoural inappropriate TSH hypersecretion.

51 : Rapid resolution of necrolytic migratory erythema after glucagonoma resection.

52 : The role of surgery in the management of islet cell tumors.

53 : Long-term survival after surgical management of neuroendocrine hepatic metastases.

54 : Surgical Management of Neuroendocrine Tumor Liver Metastases.

55 : Neuroendocrine liver metastases: a contemporary review of treatment strategies.

56 : Cytoreductive hepatic surgery for neuroendocrine tumors.

57 : Clinical Characteristics and Management of Functional Pancreatic Neuroendocrine Neoplasms: A Single Institution 20-Year Experience with 286 Patients.

58 : Prolonged survival after hepatic artery embolization in patients with midgut carcinoid syndrome.

59 : Hepatic arterial chemoembolization in patients with liver metastases of endocrine tumors. A prospective phase II study in 24 patients.

60 : Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors.

61 : Hepatic artery chemoinfusion with chemoembolization for neuroendocrine cancer with progressive hepatic metastases despite octreotide therapy.

62 : Hepatic artery chemoembolization for management of patients with advanced metastatic carcinoid tumors.

63 : Permanent transarterial embolization of neuroendocrine metastases of the liver using cyanoacrylate and lipiodol: assessment of mid- and long-term results.

64 : Transarterial chemoembolization of liver metastases from well differentiated gastroenteropancreatic endocrine tumors with doxorubicin-eluting beads: preliminary results.

65 : Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients.

66 : 90Y Radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience.

67 : Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases.

68 : Hepatic arterial chemoembolization using drug-eluting beads in gastrointestinal neuroendocrine tumor metastatic to the liver.

69 : Extrahepatic disease should not preclude transarterial chemoembolization for metastatic neuroendocrine carcinoma.

70 : Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival.

71 : Radioembolization with yttrium microspheres for neuroendocrine tumour liver metastases.

72 : Radioembolization for neuroendocrine liver metastases: safety, imaging, and long-term outcomes.

73 : Hepatic artery embolization and chemoembolization for treatment of patients with metastatic carcinoid tumors: the M.D. Anderson experience.

74 : The Role of Interventional Radiology for the Treatment of Hepatic Metastases from Neuroendocrine Tumor: An Updated Review.

75 : Operative Microwave Ablation for the Multimodal Treatment of Neuroendocrine Liver Metastases.

76 : Metastatic glucagonoma: treatment with liver transplantation.

77 : Liver transplantation for unresectable pancreatic neuroendocrine tumors with liver metastases in an era of transplant oncology.

78 : Liver transplantation for the treatment of liver metastases from neuroendocrine tumors: an analysis of the UNOS database.

79 : Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group.

80 : Lanreotide in metastatic enteropancreatic neuroendocrine tumors.

81 : Everolimus for advanced pancreatic neuroendocrine tumors.

82 : Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.

83 : Glucagonoma Pancreatic Neuroendocrine Tumor Treated With 177Lu DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy.

84 : Symptomatic and Radiological Response to 177Lu-DOTATATE for the Treatment of Functioning Pancreatic Neuroendocrine Tumors.

85 : Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas.

86 : Influence of aorto-coronary saphenous vein bypass surgery on left ventricular function. Comparison before and one year after surgery in 80 patients.

87 : Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors.

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