Dermatologic Manifestations of Glucagonoma Syndrome 

Updated: Aug 24, 2021
Author: Ali Alikhan, MD; Chief Editor: William D James, MD 

Overview

Background

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]

Pathophysiology

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.

Etiology

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.

Epidemiology

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]

Prognosis

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.

 

Presentation

History

Patients usually present with nonspecific complaints, such as weight loss, diabetes, diarrhea, and stomatitis. Unexplained weight loss and the onset of necrolytic migratory erythema (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.[12]

Physical Examination

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.[13] 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 or polycyclic 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.[14] Note the images below.

Necrolytic migratory erythema in a patient with gl Necrolytic migratory erythema in a patient with glucagonoma syndrome. Annular erythematous plaques, vesicles, and erosions involving the whole perineal area are shown.
Necrolytic migratory erythema involving the entire Necrolytic migratory erythema involving the entire buttock and perineal region in a patient with glucagonoma syndrome.
Close-up view of an annular plaque showing necroly Close-up view of an annular plaque showing necrolytic migratory erythema in a patient with glucagonoma syndrome.
 

DDx

 

Workup

Laboratory Studies

Since glucagonoma may arise in the context of a polyfunctional endocrine tumor, assessing serum glucagon, in addition to serum insulin, corticotropin, pancreatic polypeptide (PP), parathyroid hormone (PTH), gastrin, serotonin and vasoactive intestinal peptide levels, is important. A glucose tolerance test may help in delineating the degree of glucagon excess relative to insulin. Glucose intolerance may relate to tumor size and hepatic metastases.

A nutritional profile, consisting of amino acid, zinc, and essential fatty acid levels, is essential because necrolytic migratory erythema (NME) may respond to a correction of a nutrient deficit.

CBC count with differential is indicated to evaluate for a possible anemia.

Blood chemistry testing may help in detecting liver metastases.

Imaging Studies

Localization of the pancreatic primary tumor and metastatic disease is performed primarily with CT scanning, MRI, and ultrasonography. In selected cases, positron emission tomography scanning may be useful. Celiac axis angiography is considered the criterion standard for diagnosis and localization of the glucagonoma. Determination of metastatic spread can be achieved by imaging with a somatostatin analogue that identifies both the primary lesion and the tumor extent.[15, 16]

Procedures

Finding the glucagonoma, if one exists, is important. Depending on the radiographic workup results, either laparotomy with tumor resection or needle biopsy may be appropriate to obtain a histologic specimen.

A punch biopsy can demonstrate NME if the skin is sampled appropriately. Multiple biopsies from the edges of early lesions are most helpful in establishing a diagnosis.

Histologic Findings

Glucagonomas are tumors of the alpha cells of the pancreas. These tumors tend to arise in the tail of the pancreas, although they can be found anywhere within the organ. Many case reports describe the tumors as solid, well circumscribed, and encapsulated. The tumors show organized nests, islands, and occasional trabeculae. They are usually hypervascular, in contrast to pancreatic adenocarcinomas. Immunocytochemistry may be positive for glucagon, although the intensity of the stain may not correlate with the serum glucagon levels. If this method does not detect glucagon production, in situ hybridization to glucagon mRNA may be definitive. Electron microscopy shows neurosecretory granules and a well-developed, rough endoplasmic reticulum and Golgi complex.

The histologic findings of NME correlate with the clinical state of evolution of the lesion. NME initially manifests as a mild perivascular dermal lymphocytic infiltrate and epidermal spongiosis. It is helpful to take more than one biopsy, as early lesions may easily be mistaken for spongiotic dermatitis. In older lesions, The epidermis classically shows hyperparakeratosis, acanthosis, an absent granular layer, and pallor of keratinocytes in the upper layers of the epidermis (note the image below). Vacuolar degeneration and necrosis in the superficial layers result in a characteristic cleftlike detachment from the deeper epidermis. The infiltrate may also include neutrophils and eosinophils. In one study, keratinocytes in NME stained positive for Ki-67, K16, and K10, supporting changes in both differentiation and proliferation of keratinocytes.

Acanthosis with upper epidermal necrolysis from a Acanthosis with upper epidermal necrolysis from a patient with necrolytic migratory erythema and glucagonoma syndrome. Note prominent intracellular edema and loss of granular cell layer (X10).
 

Treatment

Medical Care

Most traditional chemotherapies 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 necrolytic migratory erythema (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.[17]

Transcatheter hepatic artery embolization (TAE) may induce selective necrosis of hepatic metastases by providing locally high levels of antineoplastic agents, thus sparing systemic adverse effects. TAE, in association with cisplatin-releasing gelatin microspheres, has been reported in one study for metastatic liver tumors.[18]

The somatostatin agonists octreotide and lanreotide are the drugs of choice in the treatment of patients with glucagonoma. These somatostatin analogs can be coupled to radioisotopes for both imaging and treatment applications.[19] Peptide receptor radioligand therapy (PRRT) with radiolabeled somatostatin analogue therapy has been tried with mixed results.[20]

Sunitinib, a small molecule inhibitor of multiple receptor tyrosine kinases critical for tumor growth and angiogenesis, including PDGF receptors, has been shown to be effective in treating numerous pancreatic neuroendocrine tumors but may be particularly efficacious in the treatment of glucagonomas.[21]

In pseudoglucagonoma syndrome, treating the underlying disease often resolves NME. One case report describes the successful use of octreotide for treating NME with pseudoglucagonoma.[22]

Surgical Care

Surgical resection is curative and, thus, is the treatment of choice if the tumor is localized.[23]   Often, the resection can be performed without adjunct therapy because the tumor is slow growing and tends to be encapsulated. The use of laparoscopy has been reported in a few cases.

When the tumor is disseminated, surgical management may be used for palliation while somatostatin or chemotherapeutic agents (see above) are administered. 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.

Multimodality therapy for liver metastases combining surgery, transarterial chemoembolization, percutaneous radiofrequency thermal ablation, and long-acting octreotide has been proven to be effective.[24]

Diet

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.[25]