Introduction
Insulinomas are rare, their incidence is estimated at 4/million/year (Baudin et al., 2013). They are the most common tumors of the endocrine pancreas (Sugiyama et al., 2010). They are frequently small lesions, malignant in 4-14% of cases (Baudin et al., 2013). The diagnosis of malignancy is difficult to establish, apart from tumor dissemination. Secondary locations are mainly liver and lymph nodes, more rarely bone, lung and brain (Sugiyama et al., 2010). The prognosis is poor with a survival rate of less than 10% at 2 years (Borson-Chazot et al., 2013). The aim of this study is to report malignant insulinomas encountered in our practice, describe their diagnosis circumstances, their clinical, biological and radiological features and their treatment.

Observations
Observation 1
A patient aged eighteen years without known disease was admitted for work up of hypoglycaemia revealed by neuroglucopenic signs. Hormonal assessment pleaded for an endogenous hyperinsulinism with glycaemia at 1.55mmol/l, insulinemia at 192.53µU/ml and C-peptide at 5.8ng/ml. Abdominal computed tomography and magnetic resonance imaging showed no abnormalities however, endoscopic ultrasound viewed two small pancreatic tumors with metastatic peripancreatic lymphadenopathy certifying malignancy. The patient refused surgery, so he was treated with general measures and diazoxide with partial improvement of hypoglycemic episodes.

Observation 2
A nineteen years old man without personal or family antecedent was hospitalized for hypoglycemia revealed by neuroglucopenic signs. Hormonal assessment found an endogenous hyperinsulinism with glycaemia at 2mmol/l, insulinemia at 74.64µU/ml and C-peptide superior to 7ng/ml. Pancreatic primary tumor was not visualized but the presence of multiple liver metastases at abdominal computed tomography attested malignancy. The patient was not candidate for surgery so he received symptomatic treatment with steroids and continuous glucose infusion.

Observation 3
A thirty-four years old man was admitted for exploration of hypoglycemic symptoms with predominance of neuroglucopenic signs. Examination did not note any clinical abnormality. Hormonal assessment confirmed endogenous hyperinsulinism with glycaemia at 2.2mmol/l, insulinemia at 14.8µU/ml and C-peptide at 3.42ng/ml. A pancreatic tumor was objectified in the head of the pancreas at the endoscopic ultrasound (Figure 1), CT scan (Figure 2) and MRI (Figure 3) with lymph node enlargement. The patient was operated on with complete surgical resection. Histology pleaded for a malignant insulinoma (Figure 4). Evolution was marked by regression of hypoglycemic symptoms. Two years after surgery the patient is still free of relapse.


Figure 1 Endoscopic ultrasound: Pancreatic hypoechoeic lesion


Figure 2 CT scan: Pancreatic lesion enhanced after contrast iodine injection


Figure 3 MRI: Pancreatic lesion enhanced after gadolinium injection


Figure 4 Histology: Tumoral proliferation of chromatin rich small endocrine cells with enhanced mitosis

Discussion
Insulinoma is a relatively rare tumor with an incidence of approximately 4 cases per million person-years. Insulinoma is malignant in 4-14% of cases (Baudin et al., 2013). Diagnosis of malignancy is difficult to make on histological clues and relies mainly on the presence of secondary locations either lymph node or distant locations. Typically malignant insulinoma affects patients in their fifth or sixth decade of life, our patients were younger with two out of three under twenty years. Our three patients were male whereas no sex predominance has been reported in the literature. Clinical manifestations of malignant insulinomas are similar but are more severe and frequent to those of benign insulinomas characterized by clinical hypoglycemic signs with predominance of neuroglucopenic symptoms (Placzkowski et al., 2007). Diagnosis of malignancy was made at presentation in all our patients. Actually diagnosis of metastasis is synchronous of the primitive tumor in the majority of cases and is rarely made at the time of recurrence (Zhao et al., 2010). In one of our patients primary lesion was not identifiable but malignancy was attested by the presence of liver metastasis, this may be due to a small pancreatic lesion or to extra-pancreatic location as reported by other authors (Steinmuller et al., 2008). On the biological side, malignant insulinomas are characterized by high levels of insulin and C-peptide compared to benign ones as was the case for our patients (Queiroz et al., 2006). Malignant insulinomas are in the majority of cases sporadic and are rarely linked to genetic syndromes such as multiple endocrine neoplasia type 1 or type 1 neurofibromatosis (Perren et al., 2006). Treatment of malignant insulinoma has two goals, remove or reduce the tumor burden and control hormonal secretion. Surgery is the corn stone of treatment. It may be a curative treatment in localized forms (Wiedenmann et al., 1998). Surgery should also be considered in lymph node, hepatic, abdominal and bone metastasis, trying to remove all macroscopic lesions (Begu-Le et al., 2008). Other treatment modalities can be used such as hepatic chemoembolisation, hepatic radiofrequency ablation or hepatic cryoablation for liver metastasis, and external radiation therapy for bone or cerebral metastasis. Hormonal secretion control is mandatory and should be addressed promptly given the risks of death and neurological sequelaes of severe hypoglycemia. Besides surgical removal of the tumor, general measures and anti-secretion drugs can be used. General measures consist in fractionated and frequent feeding, enteral feeding or parenteral glucose perfusion in refractory hypoglycemia. Diazoxide is the first line medical treatment for hypoglycemia. It acts by opening potassium channels and is effective in half of cases of insulinomas (Gill et al., 1997). Somatostatin analogs can be used in case of non response to diazoxide. Long term efficacy has been reported in some reports (Romeo et al., 2006). However, paradoxical hypoglycemia has been reported in some cases (Healy et al., 2007). Chemotherapy may control hormonal secretion and may also have anti- tumoral effect. Newer drugs such as the mTOR inhibitor everolimus and temozolomide seem to be more efficacious than older regimens which used 5 fluorouracil, doxorubicin and streptozotocin (Herder et al., 2011). The prognosis depends on the extension of the disease mainly the presence of liver metastasis and on the quality of hormonal secretion control. In one long-term study the 10-years survival was of 29% (Service et al., 1991).

Conclusion
Malignant insulinoma is a rare disease with poor prognosis. As in benign tumors, hypoglycemic episodes are the presenting symptoms. Diagnosis is often made late as metastases are usually present at presentation. An earlier diagnosis is important to improve the prognosis as surgery may be curative in localized disease.

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