Insulinomas are relatively rare tumors of the endocrine pancreas that cause debilitating and even life-threatening symptoms. Although insulinomas are rare, with an incidence of approximately 4 cases per 1 million person years, these tumors are the most common functional islet cell tumors of the pancreas.^1,2 Increased awareness of this condition and advances in technology over the last several decades have improved the diagnostic accuracy and facilitated treatment planning. Given the rare incidence of insulinomas and the potentially misleading clinical presentation, it is vital for the physician to have a thorough understanding of the diagnosis and management of this condition.

In general, patients with insulinoma are divided into two major categories: those who have sporadic insulinomas and those who have insulinomas secondary to a genetic syndrome such as multiple endocrine neoplasia type 1 (MEN-1). This distinction is key as it determines the diagnostic workup and surgical approach.³ The majority of patients with insulinoma (up to 90%) are in the former category and have a solitary, benign tumor in the pancreas.^1,4,5 For these patients, insulinomas may occur at any age but they are most frequently diagnosed in the fourth and fifth decades of life. Additionally, there is a slight female predominance of up to 50% to 60%.^1,4,6

However, up to 10% of patients with insulinoma have an inherited form of the disease that is typically associated with MEN-1 syndrome and these patients usually have multiple pancreatic tumors.^5–7 These patients tend to be diagnosed at a younger age (usually the mid-20s), and there is no gender predominance.⁸ They often have between 2 and 16 insulinomas, with an average of 6 to 7,^8,9 and their risk of tumor recurrence after surgical treatment is three- to fourfold higher as compared to patients without MEN-1.¹ This higher incidence of recurrence can be due to the lack of intraoperative detection of smaller tumors or incomplete removal of tumors.¹⁰

Of all insulinomas, 4% to 14% are malignant. The incidence of malignancy in patients with sporadic insulinomas ranges from 3.8% to 4.9%, whereas the incidence of malignancy in patients with MEN-1 associated insulinomas ranges from 0.42% to 0.89%.^1,6 The staging of insulinomas follows the TNM (tumor/node/metastases) staging guidelines for all neuroendocrine tumors. One of the most important predictors of survival for all neuroendocrine cancers lies in the grade of the tumor, which depends on the rate of proliferation. The proliferative index is defined by the percentage of tumor cells that are immune positive for the Ki-67 antigen (Ki-67 index) or by the mitotic rate (the number of mitoses per 10 high-power microscopic fields) with less aggressive, low-grade tumors having a lower mitotic rate and a lower proliferative index.^11,12 Overall, malignant insulinoma is associated with decreased survival rates. Specifically, the 10-year postoperative survival rate of malignant versus benign insulinomas is 29% versus 88%, respectively.^1,4,6 However, malignant insulinoma is typically an indolent tumor with potential long-term survival even in the presence of metastases.

The diagnosis of insulinoma is made based on clinical presentation and laboratory testing. The symptoms of insulinoma are classically divided into two groups: autonomic symptoms and neuropsychiatric symptoms. The former include tachycardia, diaphoresis, headache, and tremulousness. Neuropsychiatric symptoms, which are the most common symptoms in insulinoma and are experienced by up to 90% of patients, include confusion, loss of consciousness, personality changes, dizziness, amnesia for hypoglycemic events, and bizarre behavior.⁵ Up to 75% of patients present with a combination of autonomic and neuroglycopenic symptoms, while the remaining patients present with either neuroglycopenic or autonomic symptoms.⁴

Prior to the 1930s, the symptoms of hyperinsulinism were described but there was no systematic method to diagnosing hyperinsulinism specifically attributed to insulinoma.¹³ Allen O. Whipple was the first to create a specific set of criteria for the diagnosis of insulinoma in 1938. The criteria essentially demonstrated that the symptoms of neuroglycopenia occurred at the time of low blood sugar levels and that these symptoms resolved upon the administration of glucose. Whipple’s systematic approach to the diagnosis of insulinoma, initially called the “essential triad,” eventually adopted the term “Whipple’s Triad.” Specifically, the triad states the following:

1. 
   

   The hypoglycemic attack must develop while the patient is in a fasting state.

   
   
2. 
   

   At the beginning of the attack or during the attack, the 24-hour fasting blood sugar levels must be <50 mg/dL.

   
   
3. 
   

   The patient has instant resolution of neuroglycopenic symptoms upon the administration of intravenous glucose.

Additionally, Whipple proposed that all three clinical characteristics of the triad must be met prior to pursuing resection of an insulinoma.¹⁴ The cornerstone for making the diagnosis of insulinoma is a 72-hour fasting test. In this exam, the patient will fast for up to 72 hours, during which time when they develop symptoms of hypoglycemia or at the end of 72 hours if they have not developed symptoms, blood glucose, insulin, C-peptide, pro-insulin, and beta hydroxybutyrate levels are drawn. These levels aid in identifying the cause of hypoglycemia and help distinguish a focal source of insulin production (insulinoma) from an exogenous source of insulin (Table 46-1).^15,16 The C-peptide and pro-insulin levels are cleavage products of endogenous insulin production and elevated levels can rule out exogenous insulin administration. Insulin is anti-ketogenic and suppresses ketone body production. A diagnosis of insulinoma is confirmed if there are elevated plasma insulin levels, low glucose levels (or an insulin to glucose ratio greater than or equal to 0.3), increased C-peptide levels, increased pro-insulin levels, and low beta hydroxybutyrate levels.^4,17

Despite the classic triad that is associated with insulinoma, symptoms can be vague and nonspecific to the point that many patients are misdiagnosed with a variety of other pathologies, including seizure disorders, before eventually being diagnosed with insulinoma.^4,17 Patients who present with nonspecific neuroglycopenic symptoms can be labeled as anxiety-prone, neurotic, or even delusional. In addition to the nonspecific clinical presentation associated with insulinomas, the symptoms tend to wax and wane for a number of years before a patient even brings them to the attention of their physician, which can cause a significant delay in diagnosis.¹⁷ Historically, the interval from symptom onset to the diagnosis of insulinoma has ranged from 1 month to 30 years, with an average diagnosis occurring between 1 and 5 years.⁴

Once the diagnosis of insulinoma is made based on clinical presentation and laboratory studies, the next step is localization of the tumor(s). Although it was previously believed that insulinomas were more likely to be found in the distal pancreas, it has been shown that the location of insulinomas is distributed equally throughout the pancreas.¹⁸ In patients with MEN-1, localization studies are critical because of the high likelihood of multiple tumors.⁸ In contrast, sporadic insulinomas are most likely to be solitary. Historically, localizing insulinomas was done by palpation at the time of surgical resection. However, up to 70% of insulinomas are <1.5 cm in diameter and can be difficult to palpate during surgical exploration.¹⁸ Tumors that are located in the head or the uncinate process can be deep in the parenchyma and especially difficult to palpate, resulting in a negative exploration rate anywhere from 10% to 30%.^19–21 The vast improvement in localization studies such as CT, MRI, endoscopic US, and intraoperative US have made identifying insulinomas far simpler. In addition to identifying the lesion, it is critical to determine the tumor’s relation to the pancreatic duct and major vessels to help formulate a resection plan.

Transabdominal Ultrasound, CT, MRI

The first line localizing methods include transabdominal ultrasound, CT scan, and MRI. The overall success rate of localizing an insulinoma preoperatively using noninvasive imaging techniques is approximately 75%.⁶ On transabdominal ultrasound, insulinomas appear as hypoechoic, homogenous, well-demarcated nodules; however, they can be difficult to delineate in patients with a thick abdominal wall or with overlying bowel gas.²² Overall transabdominal ultrasound has a sensitivity ranging from 59% to 79% but given that it is inexpensive, noninvasive, and readily available, it is still often used as an initial localizing method.^6,18,22 On CT scan, insulinomas typically appear as hypervascular structures with contrast enhancement (Fig. 46-1). Common factors that can result in failing to localize an insulinoma using CT include lesions that are small (<2 mm), those that are in close proximity to mesenteric vessels and may be mistaken for vasculature, or those located in the pancreatic head where it may be difficult to delineate a mass from normal pancreatic nodularity.^23,24 Also, insulinomas may appear as cystic structures rather than as a solid mass or they may be pedunculated and thus be mistaken for normal pancreatic parenchyma.²⁴ The sensitivity of CT, which ranges from 63% to 69%, has improved with the evolution of technology and the use of multiphasic phases including arterial, venous, and pancreatic (a phase between the arterial and venous phases).^6,23,24 The ideal phase for identifying an insulinoma is not well defined. The pancreatic phase can be performed to better identify tumors that do not enhance early enough to be seen in the arterial phase but have already undergone contrast washout at the time of the venous phase.^24,25 On MRI, which has a sensitivity ranging from 75% to 85%, insulinomas appear as low signal intensity on T1-weighted images and high signal intensity on T2-weighted images.^6,18,26–28 The technological advances in diffusion weighted imaging has significantly increased the sensitivity of MRI and typically MRI is more accurate at localizing smaller lesions compared to CT.^23,27