Clinical Features

In 1966, McGavran and colleagues (314) called attention to a syndrome that included acquired diabetes and glucagon-producing tumors. It became apparent only later that these tumors usually were accompanied by a very characteristic skin rash. The main features of the glucagonoma syndrome include a characteristic rash termed necrolytic migratory erythema (NME) (82% of patients) (Fig.6), painful glossitis, angular stomatitis, normochromic normocytic anemia (61%), weight loss (90%), mild diabetes mellitus (80%), hypoaminoacidemia, deep vein thrombosis (50%), and depression (50%). The syndrome also goes by the acronym 4D syndrome, which stands for dermatosis, diabetes, deep vein thromboses, and depression.

The frequency of islet cell tumors has been estimated in autopsy series to be between 0.0 and 1.4% of all cases studied. In a very thorough study of 1,366 consecutive adult autopsies, Grimelius and Wilander (315) found a tumor frequency of 0.8%. All tumors were adenomas, and all contained histochemically defined glucagon cells. Although these adenomas contained glucagon, it is not known whether they were overproducing or even secreting glucagon. None of the tumors had been suspected during life. The clinical incidence of glucagonomas probably is 1% of all pancreatic neuroendocrine tumors. Analysis of the SEER data base revealed 1,310 pancreatic neurodocrine tumor patients of which 29 (2 %) were glucagonoma (Yao 2007).

The NME rash of the glucagonoma syndrome has a characteristic distribution. It usually is widespread, but major sites of involvement are the perioral and perigenital regions along with the fingers, legs, and feet. It also may occur in areas of cutaneous trauma. The basic process in the skin seems to be one of superficial epidermal necrosis, fragile blister formation, crusting, and healing with hyperpigmentation. Skin biopsies usually show small bullae containing acantholytic epidermal cells as well as neutrophils and lymphocytes(316). The adjacent epidermis usually is intact, and the dermis contains a lymphocytic perivascular infiltrate. Different stages of the cutaneous lesions may be present simultaneously. Biopsy examination of a fresh skin lesion may be the most valuable aid in suggesting the diagnosis of glucagonoma syndrome, but repeated biopsy samples may be necessary to raise this possibility. A painful glossitis manifested by an erythematous, mildly atrophic tongue has been associated with the cutaneous lesions.

Two other features of the syndrome are noteworthy. First, an alarmingly high rate of thromboembolic complications occurs in patients with glucagonomas, and many patients succumb to pulmonary embolism. Unexplained thromboembolic disease should alert one to the possibility of glucagonoma. Second, depression and other psychiatric disturbances including depression are common, but these may relate in part to the chronic dermatosis (308;317).

Several metabolic disorders are associated with cutaneous lesions closely resembling the NME of the glucagonoma syndrome. These include acrodermatitis enteropathica, zinc deficiency induced by hyperalimentation, essential fatty acid deficiency, the dermatosis of protein calorie malnutrition of kwashiorkor, and pellagra resulting from niacin deficiency (318-321). Cutaneous manifestations associated with malabsorptive states often are nonspecific, affecting approximately 20% of patients with steatorrhea. Improvement in the rash associated with the glucagonoma syndrome has been reported with amino acid repletion as well as administration of carbohydrate. The skin rash also has been shown to improve with the administration of zinc (322). Almost invariably, the dermatosis resolves after successful removal of a glucagon-producing tumor, even if the rash has been present for several years (323;324). In addition, in those patients who do not undergo curative resection but are treated with chemotherapeutic agents, dermatitis improves as the glucagon levels decrease (165;324;325).

Glucose intolerance in the glucagonoma syndrome may relate to tumor size. Fasting plasma glucagon levels tend to be higher in patients with large hepatic metastases than in those without hepatic metastases,(323) and all patients with large hepatic metastases had glucose intolerance. Massive hepatic metastases may decrease the ability of the liver to metabolize splanchnic glucagon, thus increasing peripheral plasma glucagon levels. Glucagon may not directly induce hyperglycemia, however, unless metabolism of glucose by the liver is directly compromised. Another factor may be variation in the molecular species of glucagon that is present in each case and its biologic potency (326).

In previously reported cases of glucagonoma in which plasma glucagon concentrations were measured by radioimmunoassay, fasting plasma glucagon concentrations were 2,100 ± 334 pg/mL. These levels are markedly higher than those reported in normal, fasting subjects (i.e., 150 pg/mL) or in those with other disorders causing hyperglucagonemia, including diabetes mellitus, burn injury, acute trauma, bacteremia, cirrhosis, renal failure, or Cushing’s syndrome, where fasting plasma glucagon concentrations often are elevated but less than 500 pg/mL. (Assay available at Inter Science Institute-800-255-2873). However, markedly elevated levels of glucagon (59,284 pg/ML) have been reported in the rare alpha-cell nesidioblastosis syndrome(Yu 2008).

As with other islet cell neoplasms, glucagonomas may overproduce multiple hormones. Insulin is the most common second hormone secreted by these tumors. Others include ACTH, PP, parathyroid hormone or substances with parathyroid hormone-like activity, gastrin, serotonin, VIP, and melanocyte stimulating hormone in that order of frequency.

Treatment

All reported glucagonomas with the cutaneous syndrome originated from single pancreatic tumors of considerable size (diameter 1.5–35 cm).(319;327). All tumors occurred in the tail or body of the pancreas, where A cells normally are abundant, deriving from the dorsal anlage of the pancreas. At the time of diagnosis, 62% of the tumors had metastases.

Glucagonomas not associated with the cutaneous syndrome but characterized by morphologic and/or chemical criteria are diagnosed in various ways. First, the tumor may appear as a malignant pancreatic tumor, discovered because of local growth, with or without metastases. Second, the tumor may be associated with an insulinoma, gastrinoma, or as part of the MEN-1 syndrome. The recently described glucagonoma cell adenomatosis syndrome suggests some patients may develop multiple tumors in the absence of MEN 1 syndrome or Von hippel-lindau syndrome (Henopp 2009). Glucagonoma also may occur as a single microadenoma found incidentally at autopsy in elderly patients (317).

If the diagnosis is made while the tumor is still localized, surgical resection can be curative (321;328;329). A study revealed that somatostatin receptor scintigraphy was positive in 97% of glucagonoma patients. (Kindamark 2007). Thus, SRS may be useful for the staging of these patients. In the occasional patient in whom a glucagonoma is discovered while the tumor is small and still localized, then laparoscopic approaches may be considered, as for other islet cell tumors. Even when malignant, these tumors tend to be extremely slow growing. Like others, we have been impressed with the dramatic response in these patients to both curative and major palliative resections (323). Preoperative preparation may require a period of total parenteral nutrition because of the severe weight loss induced by the catabolic effects of glucagon. Antibiotics, steroids, and both amino acid and zinc supplementation may improve the skin rash when it is severe, but cure of the rash is achieved only with the return of glucagon levels to normal. Octreotide also is useful in helping to improve the perioperative condition of these patients. Prophylactic measures to prevent venous thrombosis, including low-dose subcutaneous heparin or intermittent pneumatic compression stockings, are mandatory for all patients during the perioperative period.

In patients for whom surgery is not feasible, streptozotocin with or without 5-fluorouracil should be considered (as described later). A trial of octreotide therapy may also prove worthwhile, as most of these tumors are somatostatin receptor positive. A recent trial has reported efficacy of sunitinib (Sutent Pfizer) in decreasing progression of growth of these tumors from 5 ½ to 11 months using Recist criteria (Raymond, et al. NANETS Abstract, 2009).Patients with liver metatases not amendable to surgical resection may be considered for chemoembolization (as described later). Recently, the use of radioembolization with selective internal radiation microspheres has been described for neuroendocrine liver metatases, including glucagonoma (King 2008).

Additional References

1. Yao J, Eisner M, Leary C, Dagohoy M. Population-Based Study of Islet Cell Carcinoma. Annals of Surg Onc 2007;14(12): 3492-3500.

2. Yu R, Nissen NN, Dhall D, Heaney AP. Nesidioblastosis and Hyperplasia of Alpha Cells, Microglucagonoma, and Nonfunctioning Islet Cell Tumor of the Pancreas: Review of the Literature. Pancreas 2008 May;36(4):428-431.

3. Henopp T, Anlauf M, Schmitt A, Schlenger R. Glucagon Cell Adenomatosis: A Newly Recognized Disease of the Endocrine Pancreas. J Clin Endocrinol Metab 2009;94(1): 213-217.

4. Kindmark H, Sundin A, Granberg D, Dunder K. Endocrine Pancreatic Tumors with Glucagon Hypersecretion: A Retrospective Study of 23 Cases during 20 years. Med Oncol 2007:24(3):330-337.

5. King J, Quinn R, Glenn DM, Janssen J, Tong D. Radioembolization with Selective Internal Radiation Microspheres for Neuroendocrine Liver Metastases. Cancer 2008 Sept 1;113(5):921-929.

6. Raymond, E., Raoul, J-L., Niccoli, P., Bang, Y-J., Borbath, I., Lombard-Bohas, C., Metrakos, P., Lu, D-R., Blanckmeister, C., Vinik, A. Sunitinib versus Placebo for the Treatment of Progressive, Well-Differentiated Pancreatic Islet Cell Tumors: A Phase III, Randomized, Double-Blind Trial. Abstract – 2009 Neuroendocrine Tumor Symposium. October 2-3, 2009, Charlotte, North Carolina.