Clinical presentation largely differs between inactive glucagonoma and endocrine active tumors.

Inactive tumors merely cause local mass effects and related symptoms develop over prolonged periods of time since the tumor is growing slowly. Pancreatic function may be impaired and compression of the common bile duct may not only aggravate digestive problems but also cause jaundice. Furthermore, space-occupying processes in close proximity to the pylorus may provoke symptoms of delayed gastric emptying, i.e., early satiety, bloating, nausea and vomiting. Compression of any part of the gastrointestinal tract or liver may lead to pain in the upper abdomen.

The above described symptoms may also be caused by active glucagonoma. However, excess secretion of glucagon induces a variety of additional symptoms that constitute the glucagonoma syndrome.

Persistent hyperglycemia and diabetes mellitus result from glucagon-induced increases of blood glucose levels and may be detected during routine analyses of blood samples. Diabetes mellitus may also cause polyuria, polydipsia and recurrent infections, complaints that may prompt the patient to seek medical attention.

NME is the most characteristic symptom of glucagonoma syndrome, although it is not pathognomonic for pancreatic cancer [8]. Erythematous patches, sometimes slightly elevated and forming plaques, typically appear in face, groin, buttocks and other regions of continuous friction. NME spreads and may eventually affect large parts of the skin. Patients often claim pain and pruritus. Scaling and central clearing seems to indicate that these lesions start to heal, but vesicles and bullae may form in peripheral regions, rupture, ulcerate and become infected. The cleared center often shows residual hyperpigmentation and ulcerated peripheral areas are subsequently covered by crusts.

Thromboembolism may manifest in different ways and indeed, pulmonary embolism has been observed in individuals suffering from glucagonoma, but deep vein thrombosis is a more common symptom of this hematological disorder. Unfortunately, deep vein thrombosis is a rather common condition and thus, this finding is very unspecific. Patients presenting with deep vein thrombosis typically claim swollen legs, tenderness and pain. Erythema or cyanosis may be observed.

Neuropsychiatric symptoms induced by glucagonoma usually correspond to the distinct moods associated with depression. Episodes of sadness alternate with those marked by irritability, frustration and anxiousness. Patients may claim sleep problems.

Additionally, normochromic and normocytic anemia and weight loss are frequently diagnosed in glucagonoma patients.

Although a variety of other conditions may induce hyperglucagonemia, assessment of serum levels of glucagon is an important step towards diagnosis of glucagonoma. A healthy individual presents with glucagon concentrations of less than 200 pg/mL, and slight to moderate elevations may be caused by hypoglycemia, fasting, Cushing syndrome, abdominal trauma or acute pancreatitis. However, glucagonoma is often related with glucagon levels that exceed 1000 pg/mL by far although near-normal concentrations have also been observed [9] [10]. It is important to note that physiological concentrations of serum glucagon do not rule out glucagonoma, particularly in patients presenting with glucagonoma syndrome. On the other hand, glucagon levels > 1000 pg/mL are considered diagnostic of this pancreatic tumor.

If physical examination and results of blood sample analysis prompt the suspicion of glucagonoma, diagnostic imaging should be applied to localize the tumor, assess its size and evaluate if metastases - most metastases are detected in the liver - have already formed. Magnetic resonance imaging and abdominal computed tomography scans may be carried out to this end [10], but endoscopic sonography may constitute a sensitive alternative if the tumor measures more than a few millimeters in diameter. The latter technique may also be applied to guide biopsy procedures. Somatostatin receptor scintigraphy is very useful to detect remote metastases of pancreatic neuroendocrine tumors.

Histopathological analysis of biopsy samples immunohistochemically stained for glucagon allows for a definite confirmation of glucagonoma.

If applicable, surgical resection of the primary tumor and all metastases is the method of choice to treat and cure glucagonoma. Removal of the tumor generally alleviates all symptoms. In some cases, local lymph nodes may need to be resected.

Alternative therapeutic approaches aim at reducing glucagonoma syndrome-associated symptoms or at damaging tumor cells in situ. These therapeutic measures may cause symptoms to subside even if the primary tumor is non-resectable.

• Radiolabelled somatostatin therapy takes advantage of somatostatin receptor expression by most glucagonomas and may induce tumor regression.
• Radiofrequency ablation may also be applied.
• Systemic chemotherapy, i.e., application of dacarbazine, doxorubicin, 5-fluorouracil or combinations thereof may be indicated.
• The immunosuppressive agent everolimus has been shown to effectively inhibit tumor progression [11].
• Similar effects have been observed for lanreotide [12].
• Hepatic arterial embolization or chemoembolization may be applied to reduce blood flow to liver metastases and should cause necrosis of these tumor cells.
• Some patients may require a liver transplant.

Tumor grading and staging at the time of diagnosis largely influence the outcome. Most patients suffering from multiple endocrine neoplasia present with benign tumors that are generally rather small, are less likely to metastasize and are thus associated with a favorable prognosis and high survival rates. In contrast, the remainder of patients often suffers from malignant glucagonoma, possibly related with glucagonoma syndrome, and in more than 50% of all cases, metastases already formed when the disease is diagnosed. Diagnosis of metastasis significantly reduces the 5-year survival rate.

Most glucagonomas are sporadic, but patients suffering from multiple endocrine neoplasia have a higher risk of developing this neuroendocrine tumor. In fact, up to one out of five glucagonoma patients belongs to this risk group [4]. However, only a small share of multiple endocrine neoplasia patients develops this type of neoplasm. Multiple endocrine neoplasia is a genetic disorder. It may either result from a mutation of the MEN gene which encodes for menin, a putative tumor suppressor, or from a mutation of the RET proto-oncogene. Both are inherited with an autosomal dominant trait. However, lack of a familial history of multiple endocrine neoplasia does not rule out this condition since de novo mutations account for a significant share of cases. Most glucagonomas detected in this group of patients correspond to benign, solitary, neurocrine inactive tumors.

With regards to sporadic glucagonoma, no precise causes have been identified so far.

Pancreatic neoplasms are among the five most common causes of death due to cancer, but pancreatic neuroendocrine tumors comprise less than 2% of those tumors [5]. In total, less than 300 cases have been described today and the annual incidence is assumed to be less than 1 per 10 million people [4].

No racial predilection has been reported and initial assumptions of a female predominance could not be confirmed in later studies [1]. Although most glucagonoma patients are older than 50 years, this pancreatic tumor has also been diagnosed in adolescents and young adults [3].

While exocrine pancreatic functions are indispensable for digestion, this organ also fulfills important endocrine tasks. In detail, glucagon, insulin, somatostatin, pancreatic polypeptide and ghrelin are produced by special cells comprising the islets of Langerhans. Glucagon and insulin may be considered antagonists in blood glucose level regulation and are released from α and β cells, respectively. Of note, limited quantities of glucagon are also produced by extrapancreatic tissues, presumably by intestinal cells [6].

Under physiological conditions, glucagon release is induced by reduced concentrations of blood glucose. Glucagon mediates an increase in hepatic glycogenolysis, gluconeogenesis and lipolysis and thus augments blood sugar levels. Elevated blood glucose, in turn, impairs further glucagon secretion by means of a negative feedback mechanism. This also applies for increased levels of insulin that are induced by high levels of blood glucose.

Glucagonoma results from uncontrolled proliferation of pancreatic α cells. Moreover, degeneration of these cells is associated with a loss of sensitivity for inhibitory factors and thus, glucagon release by far exceeds physiological levels. Neither insulin nor other modulators of glucagon secretion are able to diminish the endocrine activity of the tumor and thus, the patient develops chronic hyperglycemia and secondary diabetes mellitus [7]. Although diabetes mellitus may cause a variety of other pathologies, it is not clear whether glucagon-induced hyperglycemia or other tumor-mediated effects account for necrolytic migratory erythema, anemia and those symptoms constituting the glucagonoma syndrome.

Moreover, glucagonomas are often malignant neoplasms and the majority of patients already presents metastases at the time of diagnosis. Depending on the localization of metastases, functional impairment of other organs and finally organ failure may occur.

No specific measures can be recommended to prevent glucagonoma.

Patients diagnosed with multiple neuroendocrine neoplasia may benefit from genetic counseling before deciding on having children.

Glucagonoma is a rare pancreatic, slow-growing, neuroendocrine tumor. It originates from glucagon-releasing α cells located within the endocrine part of the pancreas, the islets of Langerhans. Functionally inactive glucagonomas have to be distinguished from those tumors that produce glucagon, a hormone that induces an increase of blood glucose levels.

Inactive glucagonoma may be benign and in such cases, they disturb pancreatic function due to local mass effects [1]. Additionally, any glucagonoma may compress the common bile duct, cause jaundice and interfere with fat digestion. Liver, stomach and small intestines may also be affected by this type of pancreatic neoplasm.

In contrast, endocrine active glucagonoma provoke what is referred to as the glucagonoma syndrome, i.e., a complex of symptoms related to autonomous production of this prodiabetic hormone. The glucagonoma syndrome comprises hyperglycemia, diabetes mellitus, necrolytic migratory erythema (NME), normochromic and normocytic anemia, weight loss, thromboembolism and neuropsychiatric manifestations [2]. NME is the most typical symptom and usually affects the face; migrating erythema, vesicles and bullae that rupture and subsequently ulcerate as well as residual hyperpigmentation characterize this dermatological lesion [3]. Although these symptoms, particularly NME, should allow for an early diagnosis, lack of awareness for this disease often delays identification of the true cause of complaints. Furthermore, active glucagonoma are most likely malignant and more than half of all patients already present metastases at the time of diagnosis. This tumor preferentially metastasizes into the liver.

Glucagonoma is a rare pancreatic tumor. Its name is derived from glucagon, a hormone that acts as an antagonist to insulin in regulation of blood glucose levels.

The pancreas consists of two types of tissues: There is the exocrine pancreas that secretes digestive enzymes that reach the duodenum via special ducts. Within the exocrine pancreas there are hormone-producing islands called islets of Langerhans. Here, glucagon, insulin, somatostatin, pancreatic polypeptide and ghrelin are produced. They are released into circulation and mediate distinct effects in different target organs. α cells secrete glucagon and uncontrolled proliferation of these cells is the direct cause of glucagonoma.

Causes

Similar to other types of cancer, no precise causes of glucagonoma are known. A small share of glucagonoma patients suffers from the genetic disorder multiple endocrine neoplasia.

Symptoms

Glucagonoma may be benign or malignant, whereby benign tumors are often related to multiple endocrine neoplasia. They might not even secrete glucagon, which significantly changes the clinical presentation. Here, symptoms are restricted to local mass effects, i.e., painful compression of adjacent tissues of pancreas, liver, stomach and small intestine, possibly jaundice due to compression of the common bile duct and delayed gastric emptying because of interference with pyloric passage.

Many malignant glucagonoma release glucagon and are insensitive to control mechanisms. The affected patient presents with glucagonoma syndrome:

• Hyperglycemia and diabetes mellitus due to glucagon-mediated increase of blood sugar levels. Diabetes mellitus may manifest in excess thirst and increased quantities of urine.
• Migratory rash
• Deep vein thrombosis
• Pulmonary embolism
• Depression
• Anemia
• Weight loss

Diagnosis

Significantly increased levels of serum glucagon are highly suspicious of glucagonoma. However, some patients may present with glucagonoma syndrome and near-normal blood glucagon concentrations. Thus, either the results of blood sample analysis or of physical examination may prompt abdominal diagnostic imaging to localize a possible pancreatic tumor. Magnetic resonance imaging and computed tomography are most frequently applied to this end. If a pancreatic tumor or metastases are detected, a tissue sample needs to be obtained for histopathological analysis and definitive confirmation of glucagonoma.

Treatment

If at all possible, the pancreatic tumor should be resected. If not applicable - or in order to lower the risk of recurrence - further therapeutic measures may be taken. Directed radionuclide therapy using radiolabeled somatostatin may be indicated. Distinct drugs are available for systemic chemotherapy, e.g., dacarbazine, doxorubicin, everolimus, lanreotide and 5-fluorouracil. These therapeutic approaches may cause symptoms to subside even if the primary tumor is non-resectable.

1. Wewer Albrechtsen NJ, Challis B, Damjanov I, Holst JJ. Do glucagonomas always produce glucagon? Bosn J Basic Med Sci. 2016; 16(1):1-7.
2. Al-Faouri A, Ajarma K, Alghazawi S, Al-Rawabdeh S, Zayadeen A. Glucagonoma and Glucagonoma Syndrome: A Case Report with Review of Recent Advances in Management. Case Rep Surg. 2016; 2016:1484089.
3. Luber AJ, Ackerman LS, Culpepper KS, Buschmann CM, Koep LJ. Paediatric necrolytic migratory erythema as a presenting sign of glucagonoma syndrome. Br J Dermatol. 2016; 174(5):1092-1095.
4. Jensen RT, Cadiot G, Brandi ML, et al. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology. 2012; 95(2):98-119.
5. Anderson CW, Bennett JJ. Clinical Presentation and Diagnosis of Pancreatic Neuroendocrine Tumors. Surg Oncol Clin N Am. 2016; 25(2):363-374.
6. Lund A, Bagger JI, Wewer Albrechtsen NJ, et al. Evidence of Extrapancreatic Glucagon Secretion in Man. Diabetes. 2016; 65(3):585-597.
7. Resmini E, Minuto F, Colao A, Ferone D. Secondary diabetes associated with principal endocrinopathies: the impact of new treatment modalities. Acta Diabetol. 2009; 46(2):85-95.
8. Nakashima H, Komine M, Sasaki K, et al. Necrolytic migratory erythema without glucagonoma in a patient with short bowel syndrome. J Dermatol. 2006; 33(8):557-562.
9. Obi N, Katabami T, Obi R, Odanaka M, Sasano K, Tanaka Y. Primary malignant hepatic glucagonoma: an autopsy case. Endocr J. 2009; 56(5):715-719.
10. Lv WF, Han JK, Liu X, Wang SC, Pan BO, Xu AO. Imaging features of glucagonoma syndrome: A case report and review of the literature. Oncol Lett. 2015; 9(4):1579-1582.
11. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364(6):514-523.
12. Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014; 371(3):224-233.