A series of cases of glucagon- secreting pancreatic tumours associated with necrolytic migratory erythema, weight loss, diabetes mellitus, and stomatitis was described in 1974 when the term glucagonoma syndrome was first coined. Not all glucagonomas are symptomatic and they may be identified solely through screening of patients with MEN 1. The nutrient deficiencies arising due to hyperglucagonaemia and the secretion from the tumour of glucagon- like peptides 1 and 2, as well as cosecretion of other hormones such as pancreatic polypeptide, give rise to a spectrum of clinical features.
necrolytic Migratory erythema (NME)
NME is characterized by erythematous, well- demarcated plaques that are pruritic and painful, and often involve the intertriginous areas, perineum, and buttocks (Figure 1). This painful pruritic rash is a typical feature of the glucagonoma syndrome and one of the most common presenting signs, occurring in 82% of patients. Suspicion of the diagnosis by dermatologists, who may be the first people to see these patients has been the most common route of referral. An added clue is recent onset diabetes. Although characteristic for the glucagonoma syndrome, NME is not pathognomonic. The initial lesions of NME are erythematous plaques, which may be associated with bullae. These lesions form erosions and crusts, which eventually heal to leave central areas of hyperpigmentation and induration. The lesions demonstrate the Koebner phenomenon, i.e. occurring at sites of trauma. Skin biopsy histology reveals necrolysis of the upper dermis and vacuolization of keratinocytes. The occurrence of NME does not correlate with metastases and has been noted in 60% of patients with benign glucagonoma.
Fig1. Necrolytic migratory erythema on the back and trunk of patient with malignant glucagonoma.
The exact pathogenesis of NME remains unclear. There have been several postulated theories; the condition appears to be a multifactorial disease caused by a combination of zinc, amino acid, and fatty acid deficiencies. The glucagonoma syndrome shares a number of clinical features with vitamin B2, B3, B6, and B12 deficiency. Indeed, vitamin B deficiency may arise as a result of hyperglucagonaemia. NME has been reported following intravenous glucagon treatment, suggesting that NME may be a direct consequence of glucagon action on the skin. NME has also been associated with conditions other than glucagonoma (e.g. coeliac disease and cirrhosis); both of these conditions may have raised glucagon or glucagon- like peptides levels.
Diabetes Mellitus
Diabetes mellitus is common in sporadic glucagonomas, occurring in 55% of patients at presentation and eventually developing in 75% of cases. Of these three- quarters require insulin therapy. Although rare, diabetic ketoacidosis has been reported.
other Clinical Features
A review from the Mayo clinic of 21 patients with glucagonoma suggested that weight loss or cachexia is a common presenting com plaint, occurring in 71% of patients with metastatic glucagonoma. Similar rates of weight loss have been noted in the Hammersmith series with 72% in patients with metastases and 40% with local disease. Normocytic normochromic anaemia was noted in ap proximately a third of patients and is probably the result of direct bone marrow suppression by glucagon. Diarrhoea occurs in ap proximately one- fifth of patients with glucagonoma. Of these, half also have elevated gastrin and pancreatic polypeptide levels. Involvement of the mucous membranes may lead to the development of stomatitis, glossitis, and chelitis in a third of cases. Psychiatric symptoms occur in 20% of patients and may vary from depression to paranoid delusions. Thromboembolism is a major source of morbidity and mortality in the glucagonoma syndrome and occurs in up to 11% of cases and may account for up to 50% of deaths.
Metastases and Site of Primary tumour
Over 80% of patients with sporadic tumours have metastases at presentation. Hepatic metastases usually involve both lobes of the liver and are multiple in two- thirds of cases; of the single hepatic metastases 75% occur in the right lobe. Of primary tumours, 41% are confined to the tail of the pancreas, 14% involve the head and body, 14% occur in the head alone, and 9% in the body alone. The primary site of glucagonomas is the pancreas in 100% of cases. Sensitive imaging modalities and hepatic angiography may allow an increased detection of the primary tumour site.
