Glucagonoma Syndrome

 

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

 

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.

The cellular protein 62 has been recently found to be absent or only focally expressed in glucagonomas, in contrast to the normal pancreas. Also seen are decreased levels of p16 and p27.

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.

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.

• 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.

Males and females appear to be equally affected.

Glucagonoma usually develops in patients aged 50-59 years.

Patients usually present with nonspecific complaints, such as weight loss, diabetes, diarrhea, and stomatitis. Unexplained weight loss and the onset of NME, especially with new-onset diabetes mellitus, often hasten the correct diagnosis. Still, because mild early lesions may exhibit only subtle changes in histology and because inadequate sampling can miss the diagnostic changes, the skin eruption itself often is interpreted as a nonspecific dermatitis. It is not uncommon for several years to elapse before the correct diagnosis is found.

NME can be found anywhere on the body, although it has a predilection for the perineum, buttocks, groin, lower abdomen, and lower extremities, areas subject to greater pressure and friction. The lesions wax and wane in a cycle of about 10 days, beginning with an erythematous patch that blisters centrally, erodes, and then crusts over and heals with hyperpigmentation. The lesions are typically annular and may demonstrate confluence in severely affected areas. Patients report intense discomfort because these lesions are pruritic and painful. Other associated mucocutaneous findings include atrophic glossitis, cheilosis, onychoschizia, buccal mucosal inflammation, and, rarely, dyspareunia.

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; see 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). However, markedly elevated levels of glucagon do not necessarily produce diabetes mellitus, NME, or hypoaminoacidemia, which are the defining criteria for this syndrome.

Nonneoplastic 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. 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.

Treatment

• Most antineoplastic drugs are not effective on glucagonoma, probably due to the tumor's indolent nature. No cure by medical means has been reported, but some drug and hormone regimens may induce tumor regression or symptomatic remission of NME.
  • Streptozocin, a drug that causes selective islet cell damage, shows promise in combination with 5-fluorouracil. The combination can achieve a 60-70% response rate.
  • Dacarbazine induced remission from NME by reducing tumor burden and glucagon levels in at least one instance.⁵
  • In some patients, lanreotide, a long-acting analog of somatostatin, cleared NME rapidly, while in other patients, it was ineffective.⁶
  • Another somatostatin analog, lanreotide, with a prolonged duration of action may also be effective.
• Intermittent infusion of amino acids and fatty acids via peripheral intravenous access can provide long-term improvement of NME.⁷
• In pseudoglucagonoma syndrome, treating the underlying disease often resolves NME.

• Surgical resection of the glucagonoma is the only treatment demonstrating a cure. This surgical procedure is possible when the tumor is still localized. Because the tumor is slow growing and tends to be encapsulated, the resection can be performed without adjunct therapy. The use of laparoscopy has been reported recently in a few cases.
• When the tumor is disseminated, surgical management is used to palliate symptoms. Since NME is the major source of morbidity in glucagonoma syndrome, palliative therapies are aimed at reducing the cutaneous eruption. Tumor debulking has been shown to decrease the intensity of the cutaneous symptoms by reducing the level of serum glucagon.
• Hepatic artery embolization may induce selective necrosis of hepatic metastases.
• Liver parenchyma is less affected by this procedure because of collateral blood supply from the portal vein. Liver transplantation with pancreatectomy may be considered if it appears that the metastatic spread is confined only to the liver.

Cases of NME secondary to celiac sprue can resolve with implementation of a gluten-free diet. Deficiencies in amino acids, essential fatty acids, and zinc have been linked to NME by observation that symptoms resolve with supplementation of the deficient nutrient.⁸