The typical feature in skin biopsy is necrolysis of the upper epidermis with vacuolated keratinocytes (Fig. 9.1c). Psoriasiform epidermal hyperplasia, hypogranulosis, and thickened stratum corneum with parakeratosis as well as perivascular lymphohistiocytic infiltrate in the superficial dermis are characteristic histopathologic features [11, 14]. Similar lesions of the skin can occur in pseudoglucagonomas without pancreatic tumor, usually due to generalized malabsorption syndrome or specific nutritional deficiencies (i.e., zinc and essential fatty acids). Same aspects on skin biopsy can be found in other deficiency dermatoses, such as pellagra or acrodermatitis enteropathica [15]. Necrolytic migratory erythema may be misinterpreted as other dermatoses (pemphigoid, mucocutaneous candidiasis, psoriasis, eczema, seborrheic or contact dermatitis) [15]. Due to nonspecific aspects of the cutaneous lesions and the rarity of this kind of tumor, skin involvement precedes the diagnosis of glucagonoma of 6–8 years on average [13].

Worsening or onset of diabetes mellitus is frequent (70–87 %) due to the plasmatic secretion of glucagon [9, 13]. It can be a glucose intolerance or a diabetes necessitating oral antidiabetics or insulin and can be cured with glucagon normalization. Weight loss is usually significant, higher than 20 kg and very evocative of the disease because, in general, it is not present in case of well-differentiated, slow-growing NET. It is secondary to the hypercatabolism of glucagon and is not a prognostic factor [13]. Venous thromboembolisms occur sometimes (25 %), and few cases of dilated heart disease with improvement of the cardiac function with the decrease of the plasmatic glucagon are described [16]. Diarrhea can be present (14 %) without malabsorption but conversely with villous hypertrophy. Finally, psychiatric disorders or deficiency encephalopathies have been observed [13].

Biologically, except diabetes, normochromic and normocytic anemia is characteristic and is related to the severity of the glucagonoma syndrome [9, 17]. Hypoaminoacidemia can occur in 40 % of the glucagonoma syndrome with frequent hypoalbuminemia [9, 13].

When the clinical diagnosis of glucagonoma syndrome is suggested, it should be confirmed by the dosage of the plasma glucagon. The excessive secretion is usually obvious [9, 13]. In basal conditions, plasma glucagon is continuously increased (N, 150 pg/ml), very often greater than 1,000 pg/ml. Hyperglucagonemia less than 500 pg/ml can be observed in other pathological conditions: diabetes mellitus (except those following pancreatectomy or pancreatitis), insufficiency of glucagon catabolism (renal failure, severe liver disease), serious diseases with hypercatabolism (infections, stress, burns), and hyperglucagonemia family. However, usually, differential diagnoses in these conditions are not a problem [13, 17].

After the biological confirmation of the glucagonoma syndrome, morphological exams have to be done to localize the primary tumor, always located in the pancreas [8, 9], more often (53 %) in the tail [7, 9]. At diagnosis, the primary is usually large, greater than 3 cm in 60 % of cases and greater than 10 cm in 20 % of cases according to Guillausseau [5]. The disease is often malignant at diagnosis, mostly (80 %) with liver metastases [7–9]. For these reasons, CT scan with arterial and venous phases (Fig. 9.2a) or MRI (Fig. 9.2b) has a good diagnostic accuracy and shows a hypervascularized tumor without necessity of EUS as in smaller tumor (insulinoma or gastrinoma). Due to the presence of somatostatin receptors, somatostatin receptor scintigraphy is usually positive and can be helpful for the confirmation of the neuroendocrine origin and the staging (Fig. 9.2c, d).