Glucagonoma

Etiology

Glucagonomas originate from the alpha cells of the islets of Langerhans, which are responsible for the synthesis and secretion of glucagon. Most glucagonomas arise sporadically, although approximately 20% are associated with inherited syndromes, most notably MEN1. Given the condition's rarity, no clear etiologic factors are known.[2]

Epidemiology

Glucagonomas are exceedingly rare neoplasms, with an estimated annual incidence ranging from 0.01 to 0.1 new cases per 100,000 individuals. These tumors most commonly present in individuals between the fifth and sixth decades of life, with no significant difference in incidence between males and females.[3]

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, leading to an elevation in plasma glucose levels. The secretion of glucagon is inhibited by hyperglycemia, insulin, somatostatin, and GLP-1.[4] It also causes relaxation of the smooth muscle of the stomach, duodenum, small bowel, and colon. Other actions of glucagon include stimulating lipolysis.

Glucagonoma Syndrome

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.[5] The precise etiology of NME is not fully understood, but it is believed to be secondary to a combination of poor nutrition, low zinc levels, and inadequate amino acid levels. Diabetes results from the direct effects of glucagon. Diarrhea may occur from increased glucagon levels and co-secretion of gastrin, VIP, serotonin, or calcitonin.

Histopathology

Glucagonomas arise most commonly in the tail of the pancreas. Microscopic evaluation reveals features characteristic of well-differentiated neuroendocrine tumors, often consisting of cells with bland nuclear features and abundant cytoplasm. The architectural patterns may vary.[6] 

Pathology reporting for pancreatic neuroendocrine tumors is similar to that of other neuroendocrine tumors. A comprehensive report includes key parameters, eg, tumor size, histologic grade, and the Ki-67 proliferation index, which is a crucial marker for assessing tumor aggressiveness. Tumor grading is based on mitotic count and Ki-67 percentage, as defined by the World Health Organization (WHO) classification system. These metrics provide critical information for predicting tumor behavior and guiding clinical management.[7]

History and Physical

Clinical Features

Patients with glucagonoma typically present after a prolonged prodrome characterized by nonspecific constitutional symptoms, which can precede diagnosis by months or years. Almost all patients experience progressive, unexplained weight loss and hyperglycemia, often appearing as new onset or rapidly worsening diabetes mellitus that is resistant to increasing antihyperglycemic therapy. Characteristic cutaneous symptoms include episodic, painful eruptions that patients describe as pruritic or burning, which fluctuate with their nutritional status; this serves as an early indication of necrolytic migratory erythema.

Additional historical features may include cheilitis (inflammation of the lips), angular stomatitis (inflammation at the corners of the mouth), glossitis (inflammation of the tongue), diarrhea, and deep vein thrombosis, the latter being a result of a tumor-induced hypercoagulable state. Neuropsychiatric symptoms, particularly depression, irritability, and cognitive slowing, reflect chronic catabolic stress and low levels of amino acids in the blood, while a personal or family history of MEN1 should raise suspicion for a potential inherited cause.[8][9]

Physical Examination

A physical examination often corroborates these historical clues. The hallmark finding is NME: well-demarcated, erythematous plaques with central clearing and peripheral blistering or crusting, classically distributed over intertriginous zones, perioral skin, lower abdomen, and groin. Mucosal surfaces may reveal atrophic glossitis, angular cheilitis, and aphthous-like ulcerations. Evidence of protein-calorie malnutrition, eg, alopecia, brittle nails, and temporal muscle wasting, often coexists. Mild hepatomegaly may be appreciated due to early hepatic metastases, and an ill-defined abdominal mass can occasionally be palpated in thin individuals when the primary pancreatic lesion is large.

Dermatologic inspection should include assessment for secondary infections within NME lesions. Vascular examination may detect lower-extremity edema or cords indicative of superficial thrombophlebitis. Collectively, these findings provide a constellation that, when recognized, should prompt targeted biochemical evaluation of fasting glucagon levels and cross-sectional imaging of the pancreas and liver.[10]

Evaluation

Glucagonoma should be suspected in patients with NME and unexplained hyperglycemia.

Laboratory Studies

Patients with suspected glucagonomas should be evaluated with laboratory testing to assess for characteristic findings of this tumor, including:

• Fasting plasma glucagon: Fasting plasma glucagon levels are abnormally elevated, usually >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 varying 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 amino acids and zinc: Concentrations of amino acids and zinc should be checked to evaluate nutritional status. Laboratory abnormalities associated with glucagonoma can include hypoaminoacidemia (resulting from the targeting of amino acids into metabolic pathways in the liver by excessive hyperglucagonemia) and low zinc levels.
• Complete blood count: 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.
• MEN1 syndrome panel: Obtaining serum parathyroid hormone, gastrin, insulin, pancreatic polypeptide, serotonin, vasoactive intestinal polypeptide (VIP), prolactin, and ACTH levels is essential, as glucagonoma can rarely be associated with the MEN1 syndrome.
• Skin biopsy: 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.[11]

Imaging Studies

Tumor localization typically starts with a helical, multiphasic, contrast-enhanced computed tomography (CT) scan. The sensitivity of multiphasic CT scans is significantly high at >80% for detecting intrapancreatic neuroendocrine tumors.[11] A magnetic resonance imaging (MRI) study with contrast is performed in cases of indeterminate lesions and may have better sensitivity in detecting liver metastases.

Glucagonomas express abundant somatostatin receptors as compared to other pancreatic neuroendocrine tumors. Hence, they are suitable for localization using somatostatin analogues, eg, octreotide. Somatostatin receptor scintigraphy (SRS) was positive in 97% of patients with glucagonoma, as noted in a study by Kindmark et al.[12] SRS also has the advantage of detecting small, occult metastases within and outside the abdomen, and is therefore helpful in staging the tumor.

Functional positron emission tomography (PET) imaging techniques, utilizing DOTA peptides such as DOTATATE, DOTANOC, and DOTATOC, can be employed for the localization of non-metastatic tumors. They offer higher spatial resolution compared to SRS and provide higher sensitivity, particularly in detecting smaller lesions.

Treatment / Management

Surgical resection

Surgical resection is the only curative option in a minority of cases where the tumor is localized at the time of diagnosis.[13] The location of the tumor determines the type of pancreatic resection. The most common site of metastasis is the liver. Hepatic resection has been recommended in patients without widespread liver involvement, diffuse extrahepatic metastases, and decreased liver function.[14] Resection has led to a decrease in glucagon levels and a significant improvement in NME.(B2)

Supportive Management

The following supportive therapies may be used for symptomatic management:

• Nutritional support includes total parenteral nutrition, amino acid supplementation, and zinc supplementation to reverse the effects of malnutrition and the catabolic effects of weight loss caused by glucagon.
• Antibiotics, zinc replacement, and steroids may help alleviate NME symptoms. 
• Prophylactic anticoagulant therapy, such as heparin, is mandatory for all patients to prevent deep venous thrombosis during the perioperative period.

Management of Progressive and Metastatic Disease

Somatostatin analogues

Long-acting octreotide LAR and lanreotide depot are first-line treatments for functional glucagonoma, as they bind to somatostatin receptor subtypes 2 and 5 on pancreatic alpha cells, suppressing excessive glucagon secretion and reducing the negative effects of catabolic hormones. These therapies alleviate symptoms such as necrolytic migratory erythema, hyperglycemia, diarrhea, weight loss, and neuropsychiatric disturbances, with studies showing median progression-free survival of 14 to 20 months and biochemical response rates often exceeding 60%. For breakthrough symptoms, dose escalation or short-acting octreotide rescue injections can be utilized, and treatment is typically initiated in patients with low-volume metastatic disease or to stabilize biochemical markers before other interventions are considered.[15][16](B3)

Tyrosine kinase and mTOR-targeted therapy

Sunitinib and everolimus are approved for progressive, well-differentiated pancreatic neuroendocrine tumors, including glucagonomas. Sunitinib yields objective responses in approximately 10% of patients, resulting in a median progression-free survival of around 11 months. Everolimus offers similar outcomes by inhibiting growth signaling. These treatments are used after disease progression on somatostatin analogues or when extrahepatic metastases make liver-directed therapies unfeasible. Closely monitoring for adverse effects, such as hypertension, cytopenias, mucositis, hyperglycemia, and noninfectious pneumonitis, is essential.[17][18](A1)

Peptide receptor radionuclide therapy

Lutetium-177 DOTATATE targets the high levels of somatostatin receptor subtype 2 in most glucagonomas, delivering beta-particle radiation that induces double-strand breaks in the DNA of tumor cells. Administered in 4 intravenous cycles, 8 weeks apart, peptide receptor radionuclide therapy (PRRT) effectively controls well-differentiated metastatic neuroendocrine tumors and can extend progression-free survival beyond 2 years. PRRT has also demonstrated symptomatic improvements, including in necrolytic migratory erythema and weight stabilization, making it a valuable option for patients with somatostatin receptor–positive disease who have adequate bone marrow and kidney function following prior treatments.[19]

Liver-directed therapy

When surgical resection is not an option for hepatic metastases, transarterial methods such as bland embolization, chemoembolization, and drug-eluting bead chemoembolization can be used to occlude hepatic arterial flow, offering rapid hormonal relief and achieving nearly 70% radiographic response rates. Radiofrequency or microwave ablation is suitable for oligometastatic lesions measuring <3 cm, either alone or in combination with limited surgical resection, while yttrium-90 radioembolization is used to treat multifocal, bilobar involvement. A preprocedural infusion of octreotide can reduce the risk of hormonal crisis, and sequential treatment of both liver lobes can minimize postembolization liver dysfunction.[20]

Systemic chemotherapy

Cytotoxic therapy is recommended for patients with large, rapidly progressing, or high-grade glucagonomas that do not respond to other treatments. Alkylator regimens, eg, streptozocin with fluorouracil or doxorubicin, have response rates of 20% to 40% but are limited by nephrotoxicity and myelosuppression. Temozolomide, often combined with capecitabine in the CAPTEM protocol, has a nearly 45% response rate and offers approximately 2 years of median progression-free survival, particularly in tumors that lack the O-6-methylguanine-DNA methyltransferase enzyme. Using somatostatin analogues alongside these therapies helps maintain hormonal control and reduce biochemical flares.[21][22](A1)

Differential Diagnosis

The following differential diagnoses should also be considered when evaluating glucagonomas:

• Fasting plasma glucagon levels can be elevated in several conditions, including acute trauma, diabetes mellitus, burn injuries, sepsis, renal failure, cirrhosis, pancreatitis, and Cushing syndrome. While glucagon levels may rise in these situations, they typically remain below 500 pg/mL. One rare disorder characterized by an inactivation mutation in the glucagon receptor gene is known as Mahvash disease. This condition leads to pancreatic alpha cell hyperplasia and an increase in glucagon levels, but without accompanying symptoms.[23]
• NME is not specific to glucagonoma and can also be seen in 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 dermatosis associated with protein-calorie malnutrition.

Prognosis

Glucagonomas are usually slow-growing tumors; however, they are often advanced by the time they are diagnosed. Survival predictors include factors, eg, age, tumor grade, and the presence of distant metastases. Achieving a cure is rare once the tumor has metastasized.

According to the National Comprehensive Cancer Network guidelines, post-surgical follow-up should include a thorough medical history and physical examination, measurement of serum glucagon levels, and imaging studies such as a CT scan or MRI, within the first 3 to 12 months after surgery. After the first year, experts recommend continuing these evaluations every 6 to 12 months for up to 10 years.[24]

Complications

Glucagonoma leads to a range of complications caused by chronic glucagon hypersecretion and metastases. Persistent high levels of glucagon result in severe insulin-resistant diabetes mellitus, which can progress to ketoacidosis. This catabolic state also causes significant hypoaminoacidemia, negative nitrogen balance, and resulting cachexia, along with vitamin and zinc deficiencies that can manifest as glossitis, cheilitis, alopecia, and necrolytic migratory erythema. The latter condition often becomes secondarily infected, further increasing morbidity.[25]

Additionally, the hypercoagulability associated with excess glucagon and procoagulant factors from the tumor leads to a notably high incidence of deep vein thrombosis and pulmonary embolism, frequently requiring long-term anticoagulation.[26] Diarrhea and steatorrhea worsen malabsorption and contribute to electrolyte imbalances, while metastatic liver involvement, common at diagnosis, may result in cholestasis, portal hypertension, and liver failure. 

Neuropsychiatric effects, including depression, cognitive impairment, and irritability, arise from ongoing catabolic stress and a depletion of amino acids in the central nervous system. Lastly, extensive tumor burden or metastasis can cause gastrointestinal or biliary obstructions, gastrointestinal bleeding, or, less commonly, cardiac issues due to paraneoplastic cardiomyopathy, highlighting the need for early diagnosis and interprofessional management to lessen these systemic complications.