Updated: Dec 16, 2022
Author: Ricardo R Correa Marquez, MD, EsD, FACP, FACE, FAPCR, CMQ, ABDA, FACHT; Chief Editor: George T Griffing, MD 


Practice Essentials

A glucagonoma is a rare neuroendocrine tumor that originates almost exclusively in the pancreas and probably accounts for 1% of all neuroendocrine tumors. Malignant glucagonomas are islet cell pancreatic tumors that are discovered because of glucagonoma syndrome (in which the glucagonoma autonomously secretes glucagon), because of local mass effects, or incidentally.[1] Glucagonomas originate from the alpha-2 cells of the pancreas. Unregulated production (overproduction) of peptide hormones and growth factors, which are not normally expressed in the tissue of origin, is characteristic of neuroendocrine tumors. Abnormal production of these bioactive peptides can lead to significant systemic toxic consequences and to the promotion of further tumor growth.[2, 3]

In 75-80% of cases, the glucagonoma starts in malignant form, and in 50% of these cases, metastasis exists at diagnosis. The tumor's presence is characterized by glucagon overproduction, weight loss, hyperglycemia, diabetes mellitus, hypoaminoacidemia, normochromic and normocytic anemia, and necrolytic migratory erythema (NME), which is the most characteristic clinical sign (as opposed to symptom) of this pathology. NME presents as phlogistic damage to tissues in areas exposed to friction and pressure. See the image below.

Necrolytic migratory erythema over the back with a Necrolytic migratory erythema over the back with areas of healing and hyperpigmentation. Courtesy of Case Reports in Surgery (

 Another noteworthy feature of glucagonoma syndrome is a high rate of thromboembolic complications and consequent pulmonary embolism; this is dangerous for many patients, who can succumb to it. As NME may be the only manifestation during the development of glucagonomas that is malignant, its early recognition and correct diagnosis is very important for a better prognosis.[4]

Glucagonomas that are not associated with glucagonoma syndrome are diagnosed in various ways. The tumor may appear as a malignant pancreatic tumor discovered because of local growth, with or without metastases, or the tumor may be associated with insulinoma or gastrinoma. Glucagonoma may also occur as a single microadenoma found incidentally at autopsy in elderly patients. Similar to other islet cell tumors, the primary and metastatic lesions are slow growing.

The vast majority of glucagonomas are sporadic (80%) with the remainder associated with multiple endocrine neoplasia type 1 (MEN1), an inherited tumor predisposition syndrome, or Mahvash disease, an extremely rare cause of familial pancreatic α-cell hyperplasia and glucagonoma due to inactivating mutations in the glucagon receptor (GCGR) gene.[5]

The causes of sporadic glucagonomoas remain unknown, and it is noteworthy that some cases of NME without glucagonoma have been reported.[6]  It has been suggested that in such patients, hyponutrition, especially that resulting from a lack of vitamins and minerals, causes differentiation/proliferation modifications of keratinocytes.[7, 8]   

Treatment may vary by stage of disease. If possible, surgical resection and debulking procedures are performed, as resection is the only curative therapy. Somatostatin analogs (eg, octreotide, octreotide long-acting) are used in patients with unresectable glucagonomas. In patients with diffuse metastases, antineoplastic drugs may be useful for palliating symptoms. See Treatment and Medication.



Although the relationship between hyperglucagonemia and necrolytic migratory erythema (NME) is not clear, elevated glucagon serum levels can be found at the same time as this cutaneous manifestation of the disease. Glucagon is a peptidic hormone mostly produced from alpha-2 cells of the pancreas and, in smaller amounts, from amine precursor uptake and decarboxylation (APUD) cells in gastric and duodenal mucosa. Three known forms of this hormone exist:

  • The pancreatic form contains 29 amino acids and has a molecular weight of 3485 daltons.
  • The gastric form contains 29 amino acids and has a molecular weight of 3500 daltons.
  • The enteric form, or enteroglucagon, contains a polypeptidic chain, has a high molecular weight, and is biologically and chemically different from other hormones, although it cross-reacts with them.

Glucagon is secreted under the influence of various factors. The most important of these is the reduced blood concentration of glucose. Acetylcholine and catecholamines elevate serum levels of glucagon and somatostatin; serotonin reduces these levels. Physiologic glucagon activity includes the following:

  • Glycogenolysis activation with contemporary glycolysis inhibition and activation of the gluconeogenesis
  • Stimulation of lipolysis and catecholamine secretion
  • Inhibition of gastric secreting activity, pancreatic secreting activity, and gastrointestinal motility
  • Stimulation of urinary excretion of water and phosphates, as well as of sodium, calcium, and magnesium ions

Hyperglycemia linked to glucagonoma is a consequence of the glycogenolytic and gluconeogenic effects of glucagon. Similarly, glucagon excess (or relative glucagon excess) can be observed in diabetes mellitus and its complication, diabetic ketoacidosis.

Glucagon secretion by a tumor is independent of feedback control mechanisms; the subsequent increase in glucagon concentration in the blood produces characteristic symptoms. Diabetes mellitus occurs in patients with glucagonoma because of the lack of equilibrium between insulin production and glucagon production (which occurs when high serum levels of glucagon and normal levels of insulin exist or when insulin production is reduced and a normal glucagon level is present). However, glucagon may not induce hyperglycemia directly unless the metabolism of glucose by the liver is directly compromised.

Another factor affecting glucagon secretion may be variation in the molecular species of glucagon that is present in each case, and the biologic potency of these molecular species of glucagon. Weight loss is due to the action of glucagon on lipid and protein metabolism; increased caloric expenditure, as determined by the proteic catabolism; and the consequent increase of gluconeogenesis and ureagenesis. This mechanism is probably also responsible for the anemia and hypoaminoacidemia observed in some patients with glucagonoma. Thromboembolism, occasionally observed in patients, is attributable to the production of a molecule similar to coagulation factor X by tumor cells.

Although many theories about the pathogenesis of NME exist, the process of pathogenesis is not explained with certainty. According to one theory, NME can be caused by a tryptophan loss in cutaneous tissues because of the excess circulating glucagon. The amino acid tryptophan is responsible for the function of niacin (pellagra prevention vitamin), which regulates cell turnover, capillary tone, and the maturation of the epidermis and mucosal epithelia.

According to another theory, NME is related to the hypoalbuminemia due to glucagon excess; in fact, albumin acts as a carrier for zinc and essential fatty acids. Zinc carries out a fundamental role in the maintenance of cutaneous trophism. The mineral is also responsible for the linoleic acid desaturation and is therefore involved in prostaglandin synthesis, which could determine phlogistic damage to tissues in areas exposed to friction and pressure if it occurs in excess. NME may also occur in areas of cutaneous trauma.


A study by Yao and colleagues, based on an analysis of the Surveillance, Epidemiology, and End Results (SEER) program database between 1973–2003, reported the occurrence of a total of 2705 cases of endocrine pancreatic tumors in the United States. According to these authors, the incidence of glucagonoma is very low, with islet cell neoplasms accounting for 1.3% of pancreatic cancers.[9]

Glucagonoma probably accounts for 1% of all neuroendocrine tumors. The annual incidence rate is estimated at 1 case per 20 million population, but that is probably an underestimation because of the relative lack of specificity of the symptoms. Autopsy studies have reported the incidence of islet cell tumors with glucagon-expressing cells at approximately 1%, supporting the assertion that many of these tumors are undiagnosed and may be associated with subclinical disease.[10]

No race prevalence is known for glucagonoma. The frequency of glucagonoma in males and females is nearly equal, although a greater incidence has been reported in females. Most patients with glucagonoma are in the sixth decade of life, with a mean age of 55 years and an age range of 19-84 years.


The rate of survival after 5 years is difficult to determine because of the small number of patients who develop the disease. Glucagonomas have a slow rate of growth. Most cases start with nonspecific symptoms and the average delay in diagnosis has been reported to be 3 years.[11] Approximately 50% of cases have metastases at diagnosis; for patients in whom metastasis has occurred, the prognosis is poor. Metastasis is principally to the liver or the locoregional lymph nodes.

Like other islet cell neoplasms, glucagonomas may overproduce multiple hormones, each of which can have clinical manifestations. Insulin is the second-most-common hormone secreted by these tumors. Others include (in order of frequency) adrenocorticotropic hormone (ACTH), pancreatic polypeptide, and parathyroid hormone (PTH) or substances with activity similar to PTH, such as gastrin, serotonin, vasoactive intestinal polypeptide (VIP), and melanocyte-stimulating hormone (MSH).





Only a subset of glucagonomas produce clinical symptoms. Glucagonoma initially manifests as a nonspecific clinical scenario characterized, in most cases, by weight loss, diabetes mellitus, diarrhea, and stomatitis. The cutaneous lesions in this phase of the disease can easily be confused with nonspecific dermatitis, which occurs more often in patients with diabetes mellitus. The so-called 4D syndrome of glucagonoma consists of diabetes, dermatitis, deep venous thrombosis (DVT), and depression.

There are reports of glucagonomas presenting as acute heart failure and dilated cardiomyopathy that reverse following therapeutic normalization of circulating glucagon levels. Less commonly recognized are the paraneoplastic phenomena associated with tumor secretion of proglucagon-derived glucagonlike peptide–1 (GLP-1) and GLP-2, which may present as hyperinsulinemic hypoglycemia and marked gastrointestinal dysfunction including refractory constipation, reduced motility, and structural abnormalities of the small intestine.[12]  

Some patients suffer from mental symptoms besides depression, such as poor sleep and nervousness, or exhibit neurological symptoms, including migraine headaches, numbness or tingling, and dementia.[11]


Physical Examination

Necrolytic migratory erythema (NME) is a presenting feature in 70-80% of glucagonoma cases. Skin manifestations include (in order of appearance) maculopapular, ringed lesions and blisters that breach after a few days, as well as, possibly, pustular evolution due to bacterial superinfection. The lesions are often confluent, evolve in a period of 1-2 weeks, and are strongly pruritic and painful. They heal with hyperpigmentation.[13]  See the image below.

Necrolytic migratory erythema over the back with a Necrolytic migratory erythema over the back with areas of healing and hyperpigmentation. Courtesy of Case Reports in Surgery (

NME initially occurs in areas of the skin that are subject to friction and pressure, such as the feet and legs, the hands and forearms, and the buttocks, pubic area, groin area, and perineal area. Mucocutaneous lesions are frequently observed as atrophic glossitis, commissural cheilitis, stomatitis, balanoposthitis or vulvovaginitis, and nail and hair dystrophies.

Aside from NME, common manifestations of glucagonoma are diabetes or glucose intolerance (in 80-90% of cases) and a weight loss of 5-15 kg (in most patients).

Less common manifestations include the following:

  • Venous thromboses, in particular DVT (in approximately 40% of cases)
  • Intestinal motility alterations, with diarrhea and abdominal pains (in approximately 20% of cases)
  • Cachexia
  • Anemia
  • Scotomata and other optical disturbances
  • Psychical disturbances (eg, insomnia, depression, disorientation, lethargy, bradylalia)


Diagnostic Considerations

The poorly defined symptoms of glucagonoma sometimes make it difficult to establish a correct differential diagnosis (eg, with a pancreatic adenocarcinoma that causes weight loss, the early stages of dyspepsia, and the later stages of jaundice).

As necrolytic migratory erythema (NME) may be the only manifestation during the development of malignant glucagonomas, clinicians often misdiagnose NME as eczema, psoriasis, or contact dermatitis.[4]  

In the absence of clinical signs and symptoms of glucagonomas, other conditions associated with elevated glucagon levels include the following[14] :

  • Cirrhosis
  • Renal failure
  • Pancreatitis
  • Diabetes mellitus
  • Prolonged fasting
  • Familial hyperglucagonemia

Differential Diagnoses



Approach Considerations

If there is a clinical suspicion of glucagonoma, finding a markedly elevated serum glucagon level on a sample drawn in the morning will confirm the diagnosis. In most cases of glucagonoma, the glucagon level will be 2-3 times the upper limit of normal.


Laboratory Studies

Determining the level of glucagonemia by means of radioimmunoassay (RIA) testing is mandatory. A positive test result for glucagonoma exceeds 1000 pg/mL (reference range is 50-200 pg/mL).

Performing a fasting blood sugar and/or glucose tolerance test to establish the presence of diabetes is important. A complete blood count (CBC) with a differential count is important for evaluating whether anemia is present. Because glucagonoma can, in rare cases, be a part of multiple endocrine neoplasia type 1 (MEN1) syndrome, also check serum levels of fasting insulin, glucagon, prolactin, calcium, and vasoactive intestinal polypeptide (VIP).

Assessing the nutritional status of the patient is important in order to correct nutritional deficits resulting from glucagon excess. Tests performed must include serum concentrations of amino acids, zinc, and essential fatty acids.

Determining the level of transaminases, bilirubinemia, and alkaline phosphatase is important in order to detect hepatic metastases. The serum level of chromogranin A (CgA) has been proposed as and demonstrated to be a type of sensitivity marker (albeit a nonspecific one) for determining the presence of glucagonoma.[15] However, elevated levels of chromogranin A do not appear to assist in the diagnosis of recurrences. Stimulation tests with arginine, secretin, or tolbutamide, which rapidly stimulate plasmatic glucagon levels in patients affected by glucagonoma, are of little additional help.

The detection of telomerase and the quantification of the human telomerase reverse transcriptase (hTERT) protein subunit have been proposed for distinguishing clinically benign from malignant endocrine tumors.[16] In reported cases, primary endocrine malignant tumor showed telomerase activity. The quantification of hTERT messenger ribonucleic acid (mRNA) has been used in clinical practice to exclude malignancy.

Imaging Studies

In patients with functioning islet cell tumors, the radiologist must localize the lesion. Knowing the tumor size and location, especially with hepatic metastases, is fundamentally important when deciding on treatment.

As with other endocrine tumors of the pancreas, the diagnosis requires localization by 1 of several modalities, including angiography, computed tomography (CT) scanning, and magnetic resonance imaging (MRI). Ultrasonography is neither specific nor sensitive and has a low negative predictive value. The most frequent anatomical site is the distal pancreas (90% body and tail), making ultrasonographic identification even more difficult.[17]  CT and MRI of the pancreas can help to characterize the precise site of the tumor (localized in the pancreatic tail in 86-88% of cases).[18] In 95% of cases, the tumor appears as a single mass, with a diameter varying from 1-30 cm.

Selective angiography of the celiac tripod can localize the center of the tumor with high reliability, and simultaneously characterizes hepatic metastases. The tumor usually appears as a prominent, hypervascular area. The combination of abdominal CT and angiography provides an acceptable preoperative assessment.[18]

MRI is useful in characterizing islet cell tumors, which have marked increased signal intensity on T2-weighted images. Gadolinium enhancement in the nonnecrotic or nondegenerated areas of the tumor shows a characteristic pattern that allows differentiation of islet cell tumors from the more common pancreatic adenocarcinoma, which is hypovascular and has lower signal intensity on T2 images.

Metaiodobenzylguanidine (MIBG) scintigraphy may be helpful in detecting the primary tumor.

Positron emission tomography (PET) scanning and scintigraphic study with indium-111 octreotide (111In-D-Phe1-octreotide) or C-11 L-dihydroxyphenylalanine (11C-L-DOPA) have been used, but, because of the small number of patients with glucagonoma, estimating the true reliability of these imaging techniques has not been possible. Because the lymph node metastases and the primary tumor in the pancreatic tail cannot be observed with ultrasonography, CT scanning, or angiography, this diagnostic tool might be useful in selected patients.[19] Practically all glucagonomas studied have been somatostatin receptor positive.[20, 21]



Correctly performed biopsy of the skin during an advanced phase of the disease allows for a diagnosis of necrolytic migratory erythema. Different stages of the cutaneous lesions may be present simultaneously. Performing repetitive, multiple, and random sampling of the lesions is very helpful for diagnosis.

Based on radiologic features, a Tru-cut biopsy or laparotomy could be performed in order to obtain histologic samples.

Histologic Findings

Usually, glucagonomas arise from alpha-2 cells of the pancreatic islets and grossly appear as a single mass (80%). Approximately 80% of glucagonomas are carcinomas; the remainder are adenomas. Although the tumor is most frequently localized in the tail of the pancreas, finding it in other areas of the organ is not rare (24% in the body of pancreas, 10% in the head of the pancreas, and 20% in multiple foci throughout the pancreas). Glucagonoma is rarely found in a gastric or duodenal location.

The tumor appears as a solid, single mass of 5 cm or more that is well demarcated from the surrounding parenchyma and is encapsulated, with a rich vascular network that differentiates it from pancreatic adenocarcinomas. More rarely, a number of neoplastic lesions can be found. The tumor cells are occasionally organized in nests and strands and appear strongly glucagon positive on immunohistochemical staining. A strong cellular affinity for betacellulin, a member of the family of epidermal growth factors (EGFs), has been reported.[22] Electron microscopy shows secretory granules and an extended rough endoplasmic reticulum (RER).

The basic skin damage seems to consist of small blisters, which contain acantholytic epidermal cells, neutrophils, and lymphocytes. The surrounding epidermis is usually intact, and the dermis contains a lymphocytic perivascular infiltrate. Skin samples from the areas with early necrolytic migratory erythema show lymphocytic infiltration of the dermis, while examination of the epidermis shows focal dyskeratosis and lymphocytes. Later, lymphocytic infiltration of the dermis with neutrophils and eosinophils can be found, while the epidermis shows diffuse parakeratosis, acanthosis, loss of the granular layer, and necrosis of the superficial layers.

Metastases that are histologically similar to the primitive tumor may be in the liver (60-90%).

Images are included below.

A section of a glucagonoma mass with several fiber A section of a glucagonoma mass with several fiber bundles and solid cellular strands (125 X). Courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.
A section of a glucagonoma mass with irregular asp A section of a glucagonoma mass with irregular aspects of fiber bundles and cellular strands (400 X). Courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.


Approach Considerations

Treatment of glucagonoma may vary by stage of disease. If possible, surgical resection and debulking procedures are performed, as resection is the only curative therapy.[23, 24, 25] Control of symptoms is possible at the early stages of disease with somatostatin analogs (SSA). Peptide receptor radionuclide therapy (PRRT) with lutetium Lu 177-dota-tate (177Lu-DOTATATE; Luthera) has been proposed as a first-line therapy in patients with glucagonoma and secreting metastasis. However, since the number of glucagonoma cases is so small, it has not yet been possible to draw results on the actual benefit of this therapy, especially in terms of long-time survival.[26]

Patients with glucagonoma who have severe weight loss may require a period of total parenteral nutrition as part of the preoperative preparation. Antibiotics, corticosteroids, amino acids, and zinc supplementation may improve severe skin rash. Octreotide is also useful to help improve the perioperative condition of these patients. Prophylaxis for venous thrombosis, including and the subcutaneous administration of low-dose heparin are mandatory for all patients during the perioperative period.

In patients for whom surgery is not feasible, consider administering streptozotocin and doxorubicin or streptozotocin and 5-fluorouracil.

In patients with widespread metastases, consider hepatic artery catheterization for infusion of doxorubicin, cisplatin, and mitomycin-C. Such treatment can often produce colliquative necrosis and mass reduction. In addition, administering octreotide before, during, and after locoregional therapy may stop the crisis caused by the massive release of glucagon.

Medical Care

Some drugs can cause partial regression of a neoplastic mass or improvements in the symptoms of necrolytic migratory erythema (NME).[23]  In the literature, good results have been obtained with streptozotocin plus either doxorubicin or 5-fluorouracil, via selective damage of islet cells.[21]

Long-acting octreotide, analogous to human somatostatin, causes NME symptom regression in some, but not all, patients.[20, 21, 27, 28]

Everolimus is approved by the US Food and Drug Administration (FDA) for progressive neuroendocrine tumors located in the pancreas (PNET) that are metastatic or are not surgically resectable. Approval was based on a study that showed an increased median progression-free survival (PFS) of 11.0 months with everolimus compared with 4.6 months with placebo.[29]

Sunitinib is also approved by the FDA for PNET, on the basis of a study that was discontinued after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group but an improvement in PFS in the sunitinib group. Median PFS was 11.4 months in the sunitinib group, versus 5.5 months in the placebo group.[30]

Lanreotide (Somatuline Depot) is approved by the FDA as a once-monthly deep subcutaneous injection for unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), to improve PFS. Approval was based on the multicenter, international CLARINET trial (n=204), which demonstrated a significantly prolonged PFS in those who received lanreotide (hazard ratio, 0.47; 95% confidence interval [CI], 0.30 - 0.73; P < 0.001; log-rank test).[31]

Surgical Care


In some patients, removal of the tumor may reverse symptoms. Several authors have reported the clinical palliation of symptoms from surgical debulking of the tumor.[32]

Beyond neoplasm removal, healthy surrounding parenchyma and locoregional lymph nodes can be resected because they may be metastatic or, more rarely, the primary site of the tumor.

Laparoscopic resection has proved a safe and feasible option for treatment of pancreatic endocrine tumors in selected patients, although most published studies have been retrospective and with small patient numbers, due to the rarity of the disease.[33, 34, 35] Laparoscopic resection is used for tumors that are benign or that pose low risk of malignancy.[35]

Leakage of pancreatic juices from postoperative pancreatic fistulas (POPFs) is a common complication of pancreatic resection. Preoperative use of the somatostatin analogue pasireotide has been studied but its efficacy in reducing clinical relevant POPFs remains questionable, and its expense and adverse effects limit its usefulness.[36, 37] Placement of a drain at the time of surgery may be considered, although studies of this practice have yielded disparate results, and in any case have included only a minority of patients with neuroendocrine tumors.[38]

Given the risk of recurrence, even patients with completely resected glucagonomas require close follow-up, especially in the first 3 years after resection. Guidelines suggest maintaining follow-up for at least 10 years in most cases.[39]


Patients with liver metastases and severe symptoms caused by tumor bulk or hormone-release syndromes may benefit from procedures that reduce hepatic arterial blood flow to metastases. The videos below demonstrate bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors.

Bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors: Part 1. Courtesy of Memorial Sloan-Kettering Cancer Center.
Bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors: Part 2. Courtesy of Memorial Sloan-Kettering Cancer Center.
Postprocedure computed tompgraphy scans after bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors. Courtesy of Memorial Sloan-Kettering Cancer Center.

Hepatic arterial occlusion with embolization or chemoembolization should cause necrosis of the metastases without damaging the healthy hepatic parenchyma, which is supplied from the portal circulation.[40, 41] This treatment may also be combined with systemic chemotherapy in selected patients.


Multimodal therapeutic interventions including liver transplantation have been reported, but further studies are needed to validate such time-consuming and expensive procedures.[42]


Because glucagonomas may cause mucocutaneous lesions, endocrine disturbances, and optic and psychic disturbances, consultations may be very helpful for differential diagnosis and therapy. Consultants may include dermatologists, neurologists, endocrinologists, and ophthalmologists.


In patients with glucagonoma, providing a supplemental protein supply in order to furnish amino acids is useful. In more severe cases, such supplementation can be administered intravenously. Ingestion of essential fatty acids (eg, olive oil), zinc, vitamins, and minerals is also helpful.



Guidelines Summary

The following organizations have issued guidelines for the diagnosis and management of glucagonoma:

  • National Comprehensive Cancer Network (NCCN) [43]
  • North American Neuroendocrine Tumor Society (NANETS) [36, 38]


The NCCN guidelines recommend the following testing for the diagnosis of glucagonoma[43] :

  • Glucagon and blood glucose
  • Multiphasic computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen with or without the pelvis

The following testing may be appropriate[43] :

  • Somatostatin receptor (SSTR) positron emission tomography (PET)/CT or SSTR-PET/MRI
  • Chest CT with or without contrast
  • Endoscopic ultrasound
  • Biochemical evaluation when clinically indicated
  • Consider genetic testing and counseling for inherited genetic syndromes

Overall, the NANETS guidelines concur with the recommendations above. With regard to screening patients for inherited genetic syndromes, NANETS guidelines recommend that patients with glucagonoma undergo a thorough history (including family history) and physical examination (including skin examination) to identify symptoms and signs of multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau (VHL) syndrome, neurofibromatosis type 1 (NF1), or tuberous sclerosis complex type 1 and 2 (TSC1-2). If any of those syndromes is suggested, the patient should be referred to a medical geneticist for further evaluation.[38]   

Testing for MEN1 is indicated in patients who have any other MEN1-associated tumors such as the following[38] :

  • Pa parathyroid adenoma or multigland hyperplasia
  • Thymic or bronchial neuroendocrine tumor
  • Pituitary adenoma
  • Adrenal nodule


The NCCN's recommended treatment for symptoms and/or tumor control in locoregional disease includes octreotide long-acting release (LAR) 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. For added symptom control, octreotide 100–250 mcg SC TID can be considered. Diabetes and hyperglycemia should be treated as appropriate. The recommended surgical intervention is distal pancreatectomy, peripancreatic lymphadenectomy, and splenectomy.[43]

NANETS also recommends the somatostatin analogues octreotide or lanreotide as first-line treatment of glucagonoma and glucagonoma syndrome.[38] Localized, biochemically confirmed glucagonoma should be resected for control of the tumor and management of glucagonoma syndrome.[36]

For metastatic disease, NCCN guidelines recommend resection of metastases and primary tumor, if complete resection is possible.[43] The NANETS guideline conference reached no consensus on the benefit of resection of primary tumors in patients with metastases. The guidelines do suggest that factors to be considered in individual cases include the following[36] :

  • Location of the tumor
  • Patient age and morbidities
  • Ability to treat or avoid local complications 
  • Possibility of improved response to peptide receptor radionuclide therapy (PRRT)

For progressive disease, the NCCN guidelines recommend managing clinically significant symptoms as appropriate. Octreotide LAR or lanreotide (if the patient is not already receiving it) should be considered. Alternative options for disease progression include the following[43] :

  • Clinical trial
  • Everolimus
  • Sunitinib
  • Temozolomide with capecitabine
  • PRRT with 177Lu-dotatate (if SSTR-positive and progression on octreotide LAR or lanreotide)
  • Other cytotoxic chemotherapy
  • Consider belzutifan in the setting of germline VHL alteration
  • Consider liver-directed therapy for liver-predominant disease
  • Palliative radiation therapy for symptomatic bone metastases


Medication Summary

Somatostatin analogs (eg, octreotide, octreotide long-acting) are used in patients with unresectable glucagonomas.[20, 27, 28] In patients with diffuse metastases, antineoplastic drugs may be useful for palliating symptoms.

Somatostatin Analogs

Class Summary

These medications include drugs with a multitude of endocrine and nonendocrine effects, including the inhibition of glucagon, VIP, and GI peptides.[27]

Octreotide (Sandostatin)

Synthetic analog of the hypothalamic peptide somatostatin that inhibits the secretion of pituitary and GI hormones, inducing an increase in the intestinal absorption of water and electrolytes, a decrease in pancreatic and gastric acid secretions, and a delay in intestinal transit time. Octreotide acts primarily on somatostatin receptor subtypes II and V. It inhibits GH secretion and has a multitude of other endocrine and nonendocrine effects, including the inhibition of glucagon, VIP, and GI peptides.

Lanreotide (Somatuline Depot)

Lanreotide is an analog of somatostatin, which is a peptide inhibitor of multiple endocrine, neuroendocrine, and exocrine mechanisms. It is indicated for unresectable, well-or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival.

Antineoplastic agents

Class Summary

These medications inhibit cell growth and differentiation.

Everolimus (Afinitor)

Rapamycin-derivative kinase inhibitor. Indicated for progressive neuroendocrine tumors located in the pancreas (PNET) that are metastatic or are not surgically resectable. Reduces cell proliferation and angiogenesis by inhibition of mTOR pathway.

Sunitinib (Sutent)

Mulitkinase inhibitor that targets several tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. Inhibits platelet-derived growth factor receptors (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR1, VEGFR2, VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line–derived neurotrophic factor receptor (RET).

Indicated for progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease.

Doxorubicin (Adriamycin, Rubex)

May be helpful for the palliation of symptoms in patients with progressive disease. The dosage is related to body surface area.

Fluorouracil (Adrucil)

Useful for the palliation of symptoms in patients with progressive disease.

Streptozocin (Zanosar)

Helpful for the palliation of symptoms in patients with progressive disease. The dosage is related to body surface area. Streptozocin may sometimes cause complete disease remission. The drug's administration must be suspended only when the desired response or toxicity occurs. Streptozocin may induce severe nephrotoxic effects.

Dacarbazine (DTIC-Dome)

Administration in patients with glucagonoma not established; however, dacarbazine may be helpful for the palliation of symptoms in patients in whom surgery is not feasible. Complete disease remission has been reported in only 1 patient.