Insulinoma is a type of functional neuroendocrine tumor (NET) which manifests with hypoglycemia caused by inappropriately high secretion of insulin. It more commonly presents as a solitary benign tumor, but it can sometimes be associated with multiple endocrine neoplasia type 1 (MEN1). Patients with insulinoma have hypoglycemic episodes, more characteristically as fasting hypoglycemia. Insulinoma is usually diagnosed by biochemical testing when there is high clinical suspicion. Surgical resection is the preferred treatment choice. Localization with imaging studies is fundamental to characterize the tumor better before surgical resection. There are also other treatment options available depending on the stage and grade of the tumor.
The etiology of solitary insulinoma is not clearly understood. Normally high plasma glucose concentration would trigger the secretion of insulin from the pancreatic beta cells and vice versa. In patients with insulinoma, insulin still gets secreted, even when plasma glucose concentration is low. The hyperinsulinemia could result from an upregulated translation process due to a variant of insulin splice. When the intracellular insulin store has been filled up, insulin gets secreted to the blood. Hyperinsulinemia causes increased glycogen synthesis, decreased gluconeogenesis, and glycogenolysis, all of which attribute to hypoglycemia.
MEN1 is a disorder characterized by a predisposition to the pituitary, parathyroid, and enteropancreatic tumors. When insulinomas are associated with MEN1, a mutation in the MEN1 gene at chromosome 11q13 is typically present in most cases.
The incidence of insulinoma is around 1 to 4 per million per year. More commonly, insulinoma is a single benign tumor, and only in 5.8% of cases, it can be malignant. It can coexist with other benign tumors in 7% of the cases, and in 6% to 7.6% of the cases, it is associated with MEN1 syndrome. Surgical diagnosis happens at a median age of 47 to 50 years old.
Fasting hypoglycemia is the most characteristic finding of insulinoma, reported in 73% of the population. Around 20% of patients have both fasting and postprandial hypoglycemic symptoms. There have been increasing numbers of patients reporting only postprandial hypoglycemic symptoms, and this is more prominent in men. Weight gain occurs in most of these patients.
Hypoglycemia presents in different ways. Sympathoadrenal activation symptoms, including palpitations, tremulousness, and diaphoresis, can be seen. Severe hypoglycemia can cause neuroglycopenic symptoms, including blurry vision, confusion, seizures, or a change in behavior. Amnesia of the hypoglycemic event is common.
Insulinoma should be suspected when a patient presents with the Whipple’s triad which includes: symptoms of hypoglycemia, a documented low plasma glucose concentration, and subsequent improvement of the symptoms with the use of glucose treatment.
There are two crucial steps in evaluating an insulinoma. The first one is to establish the diagnosis with biochemical tests when there is high clinical suspicion, and the second one is to localize the tumor.
A 72-hour fast is the gold-standard test for diagnosing insulinoma. It is useful when the Whipple triad is not observable and when there were no biochemical tests during spontaneous hypoglycemic episodes.  The combination of plasma glucose concentration under 55 mg/dL, insulin level greater than or equal to 3 microUnits/mL, C peptide level greater than or equal to 0.6 ng/mL, proinsulin level greater than or equal to 5 pmol/L, beta-hydroxybutyrate level less than or equal to 2.7 mmol/L and a simultaneous negative sulfonylurea level indicates that the hypoglycemia induction is by hyperinsulinemia.
A successful preoperative localization by noninvasive modalities remains around 75%. Computed tomography (CT) with contrast is the most frequently used initial noninvasive testing. CT detects 70 to 80% of the tumors where the insulinoma usually presents as a small solid mass, which enhances after contrast. Abdominal ultrasound (US) focusing on the pancreas is sometimes preferred, given its convenience and low cost. Magnetic resonance image (MRI) detects about 85% of the insulinomas that seem to enhance homogeneously after gadolinium administration. Glucagon-like peptide-1 receptor (GLP-1) imaging is a promising new modality test and has been studied to localize insulinoma with success detection rate of 66 to 97% in some small studies.
When there is high suspicion for insulinoma with negative noninvasive studies, invasive tests such as endoscopic ultrasonography (EUS) or a selective arterial calcium stimulation test (SACST) with hepatic venous sampling could be an approach considered. EUS has a sensitivity of 70 to 95% and is superior to CT for localization.  This is the preferred test of choice if non-invasive studies are negative as it also allows tissue acquisition that can be very helpful, especially in cases that the tumor is small. SACST has a sensitivity of 93% for detecting insulinoma and could be performed when other imaging studies are negative, or in patients with MEN1 syndrome.
Histology examination and immunostaining for chromogranin A, synaptophysin, and insulin should be done to support the diagnosis of insulinoma. A Ki67 index should also be obtained for grading, especially when a patient demonstrates an aggressive clinical course.
Tumor size of greater than or equal to 2 cm, Ki67 more than 2% and molecular features including chromosomal alteration such as 3p and 6q loss and 12 q gain or chromosomal instability, are possible predictors for metastatic disease and poor progression-free survival (PFS).
Malignant insulinomas have evidence of extrapancreatic regional lymph nodes or even remote extension. Certain factors including fasting time for the occurrence of hypoglycemia being under 8 hours, higher blood insulin level (greater than or equal to 28 microUnits/mL) and higher C-peptide level (greater than or equal 4.0 ng/mL) at the glycemic nadir. These factors, as well as larger tumor size (greater than or equal to 2.5 cm), all correlate with an increased risk of malignant disease. The extent of liver metastases and the presence of lymph node metastases are important prognostic factors.
The recommendation is that all young patients with insulinoma undergo genetic testing. MEN1 syndrome should be a consideration in patients with either family and/or personal history of other endocrinopathies.
Surgical resection is recommended for local disease but it should also be considered for advanced disease. Single sporadic insulinoma is curable by surgical intervention. Surgeons have described several different surgical approaches. The most commonly used is enucleation of the insulinoma and partial distal pancreatectomy. Nowadays laparoscopic resection of insulinoma is gaining in popularity with a shorter hospital stay and at least similar favorable outcomes. Robotic enucleation of insulinoma is being reported in some cases with also good short and long-term outcomes compared to the laparoscopic approach. Patients with MEN1 might need a different surgical approach, including subtotal pancreatectomy in addition to enucleation of the tumors. EUS-guided ethanol ablation has been attempted in poor surgical candidates and has been successful in some case series.
Clinicians can attempt medical treatment before surgery in recurrent or malignant cases. For initial insulinomas, dietary modification, diazoxide, everolimus, and MedicAlert bracelets are prudent steps. Other strategies, including glucagon pen, somatostatin analogs, and steroids, are also considerations.
If the tumor is unresectable, if the patient has metastatic disease, or if he is a poor surgical candidate, diazoxide is an option. Diazoxide can decrease insulin release and enhance glycogenolysis. Around 60% of the patients become symptom-free. The efficacy of octreotide in patients with refractory hypoglycemia is less predictable but remains an option for patients who do not respond to diazoxide. For patients with refractory symptoms and stable tumor volume, adjusting the dose of octreotide or getting surgical resection could be considered.
For patients with refractory symptoms and increasing tumor volume, oncologic control with referral to specialty centers is the recommended course. For patients with well-differentiated pancreatic neuroendocrine tumors (pNET), targeted therapy (everolimus or sunitinib) are pharmaceutical options. Everolimus inhibits the mammalian target of rapamycin. Everolimus was found to improve median PFS in patients with low or intermediate-grade, advanced progressive pNET and a subgroup of functional pNET including but not limited to insulinomas. It can also help to control hypoglycemia in patients with malignant insulinoma. Lastly, sunitinib is also recommended for progressive metastatic pNET, although a small volume of patients with insulinoma participated in these studies.
For advanced disease, surgical resection could still be an option if most (90% or more) of the tumor is safely resectable, or if the liver metastases seem to be resectable. There has not been sufficient research on the different regimens of therapies to determine established choices. Cytotoxic therapies such as 5-FU or temozolomide could be possibilities in patients with advanced pNET as palliative therapy 
Some research suggests neoadjuvant therapy of peptide receptor radionuclide therapy (PRRT) in unresectable or borderline resectable pNET because of survival benefits. PRRT can also control hypoglycemia in malignant insulinomas, but its role in insulinoma treatment still needs more investigation.
Researchers have developed several classification and grading systems (WHO2010, ENETs, AJCC) for pNET. Most of them provide essential prognostic values.
Newer classification systems include WHO2017 and AJCC 8 edition. AJCC (8th edition, 2017) includes ENETs definitions for T stage and prognostic stage grouping. There is further modification of this staging system available which might provide better prognostic information.
TX - Tumor cannot be assessed
T1 - Tumor limited to the pancreas, less than 2 cm
T2 - Tumor limited to the pancreas, 2 to 4 cm
T3 - Tumor limited to the pancreas, greater than 4 cm; or tumor invading the duodenum or common bile duct
T4 - Tumor invasion of adjacent organs (e.g., stomach, spleen, colon, adrenal gland), or the walls of large vessels (celiac axis or the superior mesenteric artery)
NX - Regional lymph nodes cannot be assessed
N0 - No regional lymph node involvement
N1 - Regional lymph node involvement
M0 - No distant metastasis
M1 - Distant metastasis
M1a - Metastasis confined to the liver
M1b - Metastasis in at least one extrahepatic site (e.g., lung, ovary, nonregional lymph node, peritoneum, bone)
M1c - Both hepatic and extrahepatic metastases
In insulinoma patients, the 10-year survival rate is 88% after successful surgical removal, and 87.5% of patients get cured (being free of symptoms for at least six months) after surgery. The 10-year survival in malignant insulinomas was 29% after successful surgical removal in one study, and the 5-year survival was 24% in another. Patients with MEN1 syndrome or malignant insulinomas have a higher rate of failing initial surgery or having a recurrence of the disease. The rate of recurrence among patients with MEN1 is around 21% at 10 and 20 years, while in those without MEN 1 is reported at 5% at 10 years and 7% at 20 years.
The complications associated with insulinoma include persistent hypoglycemia causing interference with daily activities, irreversible neurocognitive impairment, and even death.
Insulinoma patients without MEN1 should have a follow-up at 3 to 6 months post resection. Biochemical testing and imaging studies should be repeated at the follow-up visit. If cured, patients can be followed as needed if they experience recurrence of symptoms. Patients with persistent symptoms after surgery might have multiple tumors or MEN1 syndrome, and they should get repeat imaging studies. Patients with multiple insulinomas, or with MEN1, should be followed yearly, even if they continued to be cured post resection.
Patients and family members should receive education about recognizing symptoms associated with hypoglycemia and also be trained to use convenient ways to correct hypoglycemia quickly. Patients should follow up with endocrinology specialists for evaluation and treatment of insulinoma. Genetic testing is sometimes necessary.
The evaluation of insulinoma includes biochemical testing and localization with imaging studies. An interprofessional team, including primary care physicians, pharmacists, radiologists, endocrinologists, surgeons, oncologists, specialty-trained nurses, and sometimes genetic specialists, could facilitate better management of insulinomas. [LEVEL V] Patient education is paramount. Length of follow up required post resection varies, and a timely adjustment of the treatment plan is more accessible if patients follow up as instructed.
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