Dermatologic Manifestations of Glucagonoma Syndrome

Glucagonoma syndrome was first described by Becker, Kahn, and Rothman in 1942. Glucagonoma syndrome is an uncommon clinicopathologic entity. ^[1] It is characterized by a glucagon-secreting tumor associated with hyperglucagonemia; necrolytic migratory erythema (NME) ^{[2, 3]} ; diabetes mellitus; hypoaminoacidemia; cheilosis; a normochromic, normocytic anemia; venous thrombosis; weight loss; and neuropsychiatric features. ^{[4, 5]} The finding of NME was once considered pathognomonic for glucagonoma syndrome. However, publications have reported that neither glucagonoma nor hyperglucagonemia is necessary for NME. ^[6] Pseudoglucagonoma syndrome refers to NME in the absence of a glucagon-secreting tumor. ^{[7, 8]}

Although the pathogenesis of NME is poorly understood, high serum levels of glucagon have been implicated in most cases. Often, NME resolves rapidly with surgical resection of a glucagonoma or with a potent inhibitor of glucagon release and glucagon action, such as somatostatin. However, abnormal serum glucagon levels alone do not explain the skin manifestations. Typically, levels of glucagon do not correlate well with the episodic course of the skin manifestations.

Various metabolic abnormalities and nutritional deficiencies also have been implicated in the pathogenesis of NME. Supplementation with both zinc and essential fatty acids has been shown to resolve NME in a small number of patients with demonstrable deficiencies of these nutrients. The role of zinc is intriguing because acrodermatitis enteropathica and acquired zinc deficiency manifest lesions similar to NME. NME also may resolve with parenteral nutrition to correct amino acid deficiencies.

In an attempt to unify these conflicting findings, some have proposed a multifactorial origin for NME. One theory asserts that the pathogenesis of NME may relate to glucagon-induced hypoalbuminemia because albumin functions as a carrier of zinc and essential fatty acids. Others suggest that zinc-dependent delta-6 desaturation of linoleic acid or poor hepatic breakdown of glucagon may contribute to an excessive prostaglandin-mediated inflammatory response in the epidermis. This theory may help to explain the distribution of the cutaneous eruption, which is more prominent in areas of increased friction and pressure.

Diabetes mellitus usually develops in the hyperglucagonemic state of glucagonoma syndrome. Because glucagon is glycogenolytic and gluconeogenic, an excess of glucagon relative to insulin elevates serum glucose levels. Therefore, the onset of diabetes occurs when insulin production fails to match glucagon production. This can be seen when either glucagon levels are very high and insulin production continues normally or insulin production is impaired and glucagon is only mildly elevated. Patient factors, such as preexisting insulin resistance, pancreatic tumor burden, and hormonal milieu (eg, tumor-derived somatostatin, other endocrine products secreted by the tumor), also modulate glucose tolerance.

Most likely, the catabolic effects of glucagon on protein and fat metabolism are the major factor causing weight loss. Increased caloric expenditure also occurs from increased gluconeogenesis and ureagenesis from glucagon-induced protein catabolism. Tumor burden and the associated cachexia probably play a minor role in weight loss. Similar catabolic effects with respect to protein metabolism probably cause the normochromic, normocytic anemia and hypoaminoacidemia that often are seen at initial presentation.

Hyperglucagonemia can be found as part of a polyfunctional endocrine tumor or an exclusively glucagon-producing tumor. The tumor may be part of a clinical syndrome (eg, Zollinger-Ellison syndrome), or it may be asymptomatic. Although most glucagonomas appear to be sporadic, in about 3% of cases they occur in the setting of multiple endocrine neoplasia type 1. Glucagonoma syndrome typically manifests with very high levels of serum glucagon (up to 1000 times normal levels).

Pancreatic neuroendocrine tumors have also been associated in patients with Von Hippel-Lindau syndrome and p27 germline mutations.

Non-neoplastic pathologies can elevate glucagon levels that are high enough to produce cutaneous manifestations. Hepatic cirrhosis is an example. Since the liver is responsible for glucagon breakdown, cirrhosis may prolong the effective plasma half-life of glucagon and contribute to abnormally high serum levels. A single report describes a case of iatrogenic hyperglucagonemia resulting from glucagon administration for congenital hyperinsulinism. ^[9] However, markedly elevated levels of glucagon alone do not necessarily produce NME, diabetes mellitus, or hypoaminoacidemia, which are the defining criteria for this syndrome. NME in the context of pseudoglucagonoma may be associated with nonpancreatic malignancy, liver disease, inflammatory bowel disease, pancreatitis, celiac sprue, and zinc and other nutritional deficiencies. Glucagon levels in pseudoglucagonoma are elevated in up to half of patients, but not to the degree as those observed with glucagonoma. ^[10]

NME with normal glucagon levels has been reported in celiac sprue and pancreatitis; similar skin findings can present with cystic fibrosis. This may be mediated by enteroglucagon, a substance that is produced by the crypt cells of the small intestine in the malabsorptive state. Unabsorbed nutrients in the lumen are a potent stimulator of enteroglucagon, which can cause NME by an undetermined mechanism.

Frequency

Glucagonomas are quite rare; since 1942, more than 300 cases have been reported worldwide. Their annual incidence has been estimated at 1 in 20 million. Pseudoglucagonoma syndrome has been described in an even smaller group of patients; data on incidence and prevalence are not currently available for this syndrome.

Sex

Males and females appear to be equally affected.

Age

Glucagonoma usually develops in patients aged 50-59 years. However, one report describes a case of glucagonoma syndrome occurring in a 15-year-old girl in the setting of multiple endocrine neoplasia. ^[11]

Glucagonomas are slow-growing tumors that typically present with nonspecific symptoms. At least 50% of these tumors are metastatic at the time of diagnosis and, therefore, generally carry a poor prognosis. The 5-year survival rate is unknown because of the small patient population, but one study reported that tumor-related death occurred in 9 out of 21 patients at an average of 4.9 years from diagnosis. The remaining 12 patients were alive after an average follow-up interval of 3.7 years. Prolonged survival (>20 y) has been reported.

The mortality rate associated with pseudoglucagonoma syndrome generally follows that of the underlying pathologic diagnosis. Some cases resulting from celiac sprue are completely reversible by dietary modification. Others, such as those resulting from hepatic cirrhosis or other neoplasm, generally have a poor outcome.