The supervised 72-hour fast is the diagnostic test of choice for an insulinoma. The protocol consists of measuring plasma glucose, insulin, C-peptide, and proinsulin levels every 6 hours until the plasma glucose level is ≤ 60 mg/dL, which is when the interval is reduced to every 1-2 hours.[2,7] The fast should be terminated when the plasma glucose level is ≤ 45 mg/dL and the patient has signs and symptoms of hypoglycemia. The diagnostic criteria from the Endocrine Society for endogenous hyperinsulinism are an insulin level ≥ 3 µIU/mL and a proinsulin level > 5 pmol/L when the plasma glucose level is < 55 mg/dL and the patient has signs and symptoms. Common diagnostic criteria for an insulinoma are:
Documentation of a blood glucose level of < 55 mg/dL with hypoglycemic symptoms
Relief of symptoms after eating
Increased plasma insulin level (≥ 3 μIU/mL)
Increased C-peptide level (≥ 0.2 nmol/L)
Increased proinsulin level (≥ 5 pmol/L)
Absence of plasma sulfonylurea
In this patient, the cause of his hypoglycemia was suggestive owing to endogenous insulin production because his insulin level was 3 µIU/mL, proinsulin was 5 pmol, and C-peptide was 1 ng/mL.
CT of the abdomen was obtained. No pancreatic lesions or concerning findings were initially reported. A meticulous review of the initial CT by two radiologists suggested a possible missed 1.8 × 1.7–cm mass at the tail of the pancreas. A multiphase CT confirmed a 1.8 × 1.7 × 1.3–cm enhancing pancreatic tail lesion (Figure 1), which raised concern for a neuroendocrine tumor, given the patient's clinical history. A gallium 68 dotatate (68Ga-DOTA) test showed uptake in the distal pancreatic mass and splenic hilum (Figure 2).
Various imaging modalities may be used to localize the tumor and to exclude or confirm metastatic disease. Three-phase CT is the preferred initial option, followed by endoscopic ultrasonography (EUS) or MRI. Glucagon-like peptide 1 receptor (GLP-1R) PET/CT is a promising new localization technique.[9,10] The GLP-1R is mainly expressed on the pancreatic beta-cells and is therefore an interesting target for imaging of previously occult insulinomas. However, in contrast to benign insulinomas, malignant insulinomas frequently lack the GLP-1R. Malignant insulinomas often do express the somatostatin receptor subtype (SSTR) 2, which can be targeted with PET/CT or PET/MRI using 68Ga-DOTA–labeled somatostatin analogs (SSAs) or with somatostatin receptor scintigraphy and single-photon emission CT (SPECT). If all localization and regionalization techniques fail to localize a tumor, intraoperative palpation of the pancreas and ultrasonography might prove to be successful.[11,12]
Treatment includes initial stabilization of the patient with intravenous dextrose, diazoxide, and octreotide if needed. For solitary tumors, surgical excision is the treatment of choice. In patients with malignant tumors, debulking of the pancreatic neuroendocrine tumors, including locoregional lymph nodes, can be considered. If hyperinsulinemia and hypoglycemia persist, diazoxide (150-200 mg in two or three divided doses per day, which can be titrated to a maximum dose of 400 mg/d) with a thiazide diuretic can be used for hypoglycemic relief. Octreotide is another medical option that lowers plasma insulin levels and alleviates symptoms in about 50% of patients.[13,14] Octreotide has a half-life of approximately 100 minutes and is typically administered in doses of 50 or 100 μg every 12 hours.
Liver metastases can be resected or treated by embolization, radioembolization (selective internal radiation therapy), radiofrequency ablation, microwave and cryoablation, high-intensity focused ultrasound, laser therapy, brachytherapy, and irreversible electroporation, depending on local availability.[7,15,16,17] In patients with unresectable, low-grade, metastatic malignant insulinomas, the long-acting somatostatin analog lanreotide autogel is the approved first-line therapy for control of tumor growth. In addition, control of hypoglycemia is sometimes achieved with this drug. If indicated, peptide receptor radiotherapy with radiolabeled SSAs or everolimus can be used for tumor, symptom, and biochemical control. Malignant neuroendocrine tumors, particularly those with a high tumor grade, can also be treated with cytotoxic chemotherapy regimens.[1,19]
The patient in this case underwent distal pancreatectomy with splenectomy. Pathology reports showed a low-grade pancreatic neuroendocrine tumor in the pancreatic tail, with a negative tumor margin and no lymphadenopathy. The specimen was stained positive for insulin (Figure 3). The patient's hypoglycemia resolved postoperatively, and plasma glucose level remains normal on subsequent follow-up.
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