**1. Introduction**

Insulinomas are rare endocrine tumours developed from pancreatic beta cells. Their incidence is about 1 in 250,000 patient-years (Cryer 2008) (0.396 per 100,000 person-years for two decades, 1967-1986) (Service et al. 1991). The median age at surgical diagnosis was found to be 47 years (8 to 82), 59% being female patients. In a series of 33 patients, the age at the time of diagnosis was 57 +/- 16 years (mean +/- SD) (range: 18-85 years) and 66% were female patients (Vezzosi et al. 2007). 90% of insulinomas are single, benign and sporadic tumours that are located in the pancreas. The diagnostic and therapeutic strategy of benign sporadic insulinomas has been now established by a recent expert consensus (Cryer et al. 2009). However, some issues remain unaddressed regarding the diagnosis and the treatment of insulinomas. More rarely, in about 10% of insulinoma patients, the insulinoma is part of MEN-1. Such patients often present with multiple insulinomas and other secreting or non-secreting endocrine tumours. Finally, a particular condition is malignant insulinoma, also found in about 10% of insulinoma patients. There are no recommendations regarding the particular conditions represented by insulinomas in MEN-1 and malignant insulinomas.

The aim of this chapter is to give an updated and detailed view of the medical management of adult patients with insulinoma regarding the diagnosis (diagnosis of hypoglycemia related to endogenous hyperinsulinism, differential diagnosis, topographic assessment) and the treatment (surgery, medical therapies), including the therapeutic strategy and the possibilities of long-term medical treatment in inoperable patients. The first part of the chapter will be focused on the most frequent case, i.e. single benign sporadic insulinoma. The remaining parts of the chapter will deal with specific issues and concerns regarding malignant insulinomas, insulinomas in genetic disorders, and the rare cases of nesidioblastosis in the adults.

<sup>\*</sup> D. Vezzosi1, A. Bennet1, J.C. Maiza1, A. Buffet1, S. Grunenwald1, J. Fauvel2, F. Courbon3, P. Otal4, N. Carrere5 and Ph. Caron1

*<sup>1</sup>Department of Endocrinology and Metabolic Diseases, CHU Larrey,* 

*<sup>2</sup>Laboratory of Biochemistry, IFB, CHU Purpan,* 

*<sup>3</sup>Department of Nuclear Medicine, CHU Rangueil,* 

*<sup>4</sup>Department of Radiology, CHU Rangueil,* 

*<sup>5</sup>Department of Surgery, CHU Purpan, Toulouse, France*.

Diagnosis and Treatment of Insulinomas in the Adults 137

The threshold to define hypoglycemia remains controversial. According to recent expert recommendations (Cryer et al. 2009) a 0.55 g/L threshold must be selected. However, the glycaemic threshold that can cause clinical symptoms is very different among individuals, and a plasma concentration of glucose below 0.7 g/L at the time of clinical symptoms is thought be enough, if the other criteria of Whipple's triad are fulfilled, to warrant further investigation. A plasma glucose concentration above 0.7 g/L during a symptomatic episode

Since even values below 0.55 g/L can be found in some healthy individuals, it is also recommended by the expert consensus that such levels be taken into account for further evaluation only in patients who had presented Whipple's triad. On the other hand, very rare insulinoma patients were found to be asymptomatic and did not fulfil Whipple's triad. Among our patients (Vezzosi et al. 2007), the diagnosis of insulinoma was made on the basis of repeated plasma glucose concentrations of 0.40-0.55 g/l after overnight fasts in one patient, though she never described any clinical symptom. In many insulinoma patients, the glycaemic threshold for clinical symptoms is shifted to very low glucose levels, so that they may be asymptomatic at the time of plasma glucose concentrations below 0.55 and even 0.45 g/L; most of these patients experienced some clinical symptoms suggestive of hypoglycaemia, but even if they present with fasting glucose levels below 0.55 g/L, Whipple's triad has not been assessed in most of them, and awaiting Whipple's triad to be fulfilled would make the diagnosis be delayed. The finding of a spontaneous plasma glucose concentration below 0.55 g/L is rare in normal subjects; during a 72-hour fast test, plasma glucose concentrations do not reach values below 0.45 g/L in most controls, and do not drop below 0.4 g/L in controls (Vezzosi et al. 2007). Therefore we think that patients with spontaneous plasma glucose concentrations below 0.55 g/L warrant further investigation, even when they do not fulfil all the criteria of Whipple's triad, and that such evaluation is mandatory in patients with plasma concentrations below 0.45 g/L, provided that plasma

Confirmation of hypoglycaemia in a venous sample is the first requirement for the

If a venous sample cannot be collected when hypoglycaemia occurs spontaneously, a 72

A detailed protocol for the fast test has first been described by the Mayo Clinic group (Service 1995)(Service 1999) and more recently by an expert consensus (Cryer et al. 2009). The patient is allowed to drink calorie-free beverages. Samples are to be collected every 6 hours until the plasma glucose concentration is less than 0.6 g/L if the patient remains asymptomatic, then the frequency of sampling is increased (every 1 or 2 hours). Serum insulin, C-peptide, proinsulin and beta-hydroxy-butyrate are to be measured in all the samples taken at the time when plasma glucose concentration drops below 0.6 g/L. At the end of the fast test, a sample is collected to measure oral hypoglycaemic agents; a glucagon test (1.0 mg intravenously) has

The criteria used to decide to stop the fast test before 72 hours have been modified recently. According to previous recommendations (Service 1995), the fast test is to be stopped if the patient has symptomatic hypoglycaemia with a plasma glucose concentration of 0.45 g/l or less, or if the plasma glucose concentration drops below 0.4 g/L. According to the recent recommendations (Cryer et al. 2009) the fast test can be stopped: 1) when Whipple's triad is observed; 2) when plasma glucose concentrations drop below 0.55 g/L in a patient who had previously experienced Whipple's triad; 3) if plasma beta-hydroxy-butyrate levels rise

indicates that those symptoms are not the result of hypoglycaemia.

glucose concentration has been measured reliably in a venous sample.

also been recommended. Insulin antibodies should also be measured.

biological diagnosis of insulinoma.

hour-fast test is to be performed.

above 2.7 mmol/L.
