Insulinoma

Insulinomas are the most common cause of hypoglycemia resulting from endogenous hyperinsulinism. In a large single-center series of 125 patients with neuroendocrine tumors, insulinomas constituted the majority of cases (55%), followed by gastrinomas (36%), VIPomas (vasoactive intestinal polypeptide tumor) (5%), and glucagonomas (3%).[11]

In 1927, Wilder established the association between hyperinsulinism and a functional islet cell tumor.[12] In 1929, Graham achieved the first surgical cure of an islet cell adenoma. Insulinomas can be difficult to diagnose. It was not uncommon for patients to have been misdiagnosed with psychiatric illnesses or seizure disorders before insulinoma was recognized.

An insulinoma is a neuroendocrine tumor, deriving mainly from pancreatic islet cells, that secretes insulin. Some insulinomas also secrete other hormones, such as gastrin, 5-hydroxyindolic acid, adrenocorticotropic hormone (ACTH), glucagon, human chorionic gonadotropin, and somatostatin. The tumor may secrete insulin in short bursts, causing wide fluctuations in blood levels.

About 90% of insulinomas are benign. Approximately 10% of insulinomas are malignant (metastases are present). Approximately 10% of patients have multiple insulinomas; of patients with multiple insulinomas, 50% have multiple endocrine neoplasia type 1 (MEN 1). Insulinomas are associated with MEN 1 in 5% of patients. On the other hand, 21% of patients with MEN 1 develop insulinomas. Because of the association of insulinomas with MEN 1, consideration should be given to screening family members of insulinoma patients for MEN 1.[13]

An in vitro study by Henquin et al identified three distinct patterns of insulin secretion by insulinomas, as follows[14] :

• Group A – Qualitatively normal responses to absence or excess levels of glucose, leucine, diazoxide, tolbutamide, and extracellular calcium chloride (CaCl ₂); concentration-dependent effect of glucose, but excessive insulin secretion in both low- and high-glucose conditions
• Group B – Large insulin responses to 1 mmol/L glucose, resulting in very high basal secretion rates inhibited by diazoxide and restored by tolbutamide but not further augmented by other agents, except for high levels of CaCl
• Group C – Very low rates of insulin secretion and virtually no response to stimuli (including high CaCl ₂ concentration) and inhibitors (with CaCl ₂ omission paradoxically stimulatory).

Increased expression of the phosphorylated mechanistic target of rapamycin (p-mTOR) signaling pathway and its downstream serine/threonine kinase p70S6k has been observed in insulinoma tumor specimens.[15] This discovery has led to studies exploring mTOR inhibitors as new therapeutic options.

United States

Insulinomas are the most common functional pancreatic endocrine tumors. The incidence is 1-32 cases per million persons per year.[16] Insulinomas comprise 55% of functional pancreatic neuroendocrine tumors.

International

One source from Northern Ireland reported an annual incidence of 1 case per million persons. A study from Iran found 68 cases in a time span of 20 years in a university in Tehran.[17] A 10-year single-institution study from Spain of 49 consecutive patients who underwent laparoscopic surgery for neuroendocrine pancreatic tumors included 23 cases of insulinoma.[9] These reports may be an underestimate.

Pancreatic fistula is the most common major complication of surgery for insulinoma,[18]  Other surgical complications include pseudocyst, intra-abdominal abscess, pancreatitis, hemorrhage, and diabetes. In one systematic review of 6222 cases, the overall surgical mortality for insulinoma was 3.7%, primarily in patients with malignant, metastatic disease undergoing open surgery. Mortality was not seen in patients undergoing laparoscopic resection.[19] The median survival in patients with metastatic disease to the liver ranges from 16-26 months.

Insulinomas have been reported in persons of all races. No racial predilection appears to exist.

Overall, the male-to-female ratio for insulinomas is 2:3 and the median age at diagnosis is about 47 years. In insulinoma patients with MEN 1, however, more cases are reported in men than in women, and the median age is younger.[10]

Features of the history in patients with insulinoma are as follows:

• About 85% of patients present with symptoms of hypoglycemia that include diplopia, blurred vision, palpitations, or weakness.

• Other symptoms include confusion, abnormal behavior, unconsciousness, or amnesia.

• About 12% of patients have grand mal seizures.

• Adrenergic symptoms (hypoglycemia causes adrenalin release) include weakness, sweating, tachycardia, palpitations, and hunger.

• Symptoms may be present from 1 week to as long as several decades prior to the diagnosis (1 mo to 30 y, median 24 mo, as found in a large series of 59 patients).[20] Symptoms may occur most frequently at night or in the early morning hours.

• Hypoglycemia usually occurs several hours after a meal.

• In severe cases, symptoms may develop in the postprandial period. Symptoms can be aggravated by exercise, alcohol, hypocaloric diet, and treatment with sulfonylureas.

• Weight gain occurs in 20-40% of cases, because patients may eat frequently to avoid symptoms.

• Case reports describe patients with type 2 diabetes who develop hypoglycemia from insulinoma[21, 22]

• Symptoms caused by effects of local tumor mass are very rare in insulinoma.

Most patients with insulinoma have normal physical examination findings. Obesity is common, for the reason cited above.

The genetic changes in neuroendocrine tumors are under investigation.[23] The gene of multiple endocrine neoplasia type 1, an autosomal dominant disease, is called MEN1 and maps to band 11q13. MEN1 is thought to function as a tumor suppressor gene. Data suggest that the MEN1 gene also is involved in the pathogenesis of at least one third of sporadic neuroendocrine tumors. Researchers were able to detect loss of heterozygosity in band 11q13 in DNA samples from resected insulinoma tissue by using fluorescent microsatellite analysis.

In a study of 12 children with insulinoma, four cases showed heterozygous mutations of MEN1 on 11q. Aneuploidy of chromosome 11 and other chromosomes was common in both MEN1 and non-MEN1 insulinomas.[24]

One study showed k-ras mutation to be present in 23% of insulinomas.[23] Another study found T372R mutations in the YY1 gene in 30% of sporadic insulinomas.[25]

The classic hallmark of insulinomas is the Whipple triad, which consists of the following:[18]

• Symptoms of hypoglycemia, especially with fasting or exercise
• Documented low blood sugar at the time symptoms are present
• Reversal of symptoms by glucose administration

Common diagnostic criteria include documentation of blood glucose level < 50 mg/dL (2.775 mmol/L) with hypoglycemic symptoms, with relief of symptoms after eating, and absence of sulfonylurea on plasma assays. The classic diagnostic criteria also include demonstration of the following during a supervised fast:

• Increased plasma insulin level (≥6 μU/ml)
• Increased C peptide level (≥0.2 nmol/l)
• Increased proinsulin level (≥5 pmol/l)

Once the diagnosis of insulinoma has been established biochemically, imaging studies are used to localize the tumor.

Failure of endogenous insulin secretion to be suppressed by hypoglycemia is the hallmark of an insulinoma. Thus, the finding of inappropriately elevated levels of insulin in the face of hypoglycemia is the key to diagnosis. Considering the reference range, the fasting plasma levels of insulin, C-peptide, and, to a lesser degree, proinsulin need not be elevated in insulinoma patients in absolute terms.

A prolonged supervised fast in hospitalized patients provides the most reliable results. During this test, levels of plasma glucose, insulin, C peptide, and proinsulin are measured every 6 hours until the plasma glucose level falls to 60 mg/dl or less, at which point the testing interval is reduced to every 1–2 h. The fast is terminated when the plasma glucose level is 45 mg/dl or less and the patient has symptoms and signs of hypoglycemia

Traditionally, a 72-hour fast has been used. However, with current assays, 90–95% of insulinomas can be diagnosed with a supervised fast of 48 hours.[18]

The calculation of ratios of insulin (µU/mL) to plasma glucose (mg/dL) during the fast is diagnostic: Healthy patients maintain a ratio of less than 0.25 (obese patients may have a slightly higher rate), whereas in patients with insulinoma, the ratio rises during fasting.

In a study from the Netherlands, a positive Whipple triad on a prolonged fasting test, in combination with an insulin/C-peptide ratio < 1, had a sensitivity of 88.9% and a specificity of 100% for the diagnosis of insulinoma.[34]

The biochemical diagnosis is established in 95% of patients during prolonged fasting when the following parameters are found:

• Serum insulin levels of 10 µU/mL or more (normal < 6 µU/mL)
• Glucose levels of less than 40 mg/dL
• C-peptide levels exceeding 2.5 ng/mL (normal < 2 ng/mL)
• Proinsulin levels ≥22 pmol/L, ^[35] or greater than 25% (or up to 90%) that of immunoreactive insulin

If these studies confirm elevated endogenous insulin, insulin antibody levels should also be checked to rule out autoimmune disease.

Stimulation tests are no longer recommended. The intravenous administration of tolbutamide, glucagon, or calcium can be hazardous, as it may induce prolonged and refractory hypoglycemia.

The presence of multiple endocrine neoplasia type 1 (MEN 1) must be evaluated by excluding the following:

• Hyperprolactinemia due to a pituitary adenoma
• Hyperparathyroidism due to parathyroid hyperplasia
• Hypergastrinemia due to a gastrinoma

Start imaging studies only after the diagnosis has been confirmed biochemically, because 80% of insulinomas are less than 2 cm in size and may not be visible by computed tomography (CT) scanning or transabdominal ultrasonography.

Successful preoperative tumor localization is achieved in about 60% of patients.[36] Some experienced surgeons perform only transabdominal ultrasound preoperatively. Other surgeons argue that the preoperative localization of insulinomas is not necessary at all because surgical exploration and intraoperative ultrasonography identify more than 90% of tumors.[37] Thus, the extent to which one attempts to define the anatomy of the beta cell lesion before surgery is a matter of judgment.

Computed tomography and magnetic resonance imaging

Helical or multislice CT has 82-94% sensitivity. In one study, dual-phase helical CT proved more sensitive than single-phase for detection of insulinoma; in addition, image acquisition in the arterial phase proved more helpful than acquisition during the portal-venous phase.[38] See the image below.

CT scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (Yeo, 1993).

Zhu et al reported that the addition of whole-pancreas perfusion to biphasic contrast-enhanced CT (CECT) may improve the detection of insulinomas. In their study of 79 consecutive cases, mean blood flow values of both insulinomas and insulinoma-harboring regions were statistically significantly higher (P < 0.01, for both) than those of tumor-free pancreatic parenchyma. The addition of perfusion allowed correct diagnosis of nine of 46 tumors (19.6%) in which biphasic CT was negative or indeterminate.[39]

In a subsequent prospective study, however, Zhu et al reported that volume perfusion CT (VPCT) is significantly more accurate than CECT for insulinoma detection, and 3 Tesla magnetic resonance imaging (3T MRI) with diffusion-weighted imaging (DWI) is better still. Lesions were more conspicuous on MRI than on VPCT, and conspicuity with both was better than with CECT. Tumor-to–pancreatic duct distance was better appreciated on MRI than on VPCT and CECT.[6]

Arteriography

The accuracy of selective arteriography varies but is around 60% in the best hands. Arteriography with catheterization of small arterial branches of the celiac system combined with calcium injections (which stimulate insulin release from neoplastic tissue but not from normal islets), and simultaneous measurements of hepatic vein insulin during each selective calcium injection localizes tumors in 90% of patients.[7]

Nuclear medicine

Insulinomas have been shown to have a very high density of glucagon-like peptide–1 (GLP-1) receptors, and radiolabeling GLP-1 analogs (eg, exendin-4) with appropriate radioisotopes can provide noninvasive localization of benign insulinomas.[40, 41] For example, indium-111 (111In)–labeled exendin-4 (111In-DOTA-exendin-4) has successfully been used to localize small insulinomas both preoperatively and, with the use of a gamma probe, intraoperatively.[42] Luo et al reported that PET/CT scanning with gallium-68 (68Ga)-NOTA–exendin-4 correctly detected insulinomas in 42 of 43 patients.[43]

Malignant insulinomas can be missed by GLP-1 target imaging because these tumors often lack GLP-1 receptors. However, these tumors often express somatostatin receptor subtype 2 (SSTR2), which can be detected with indium-111 (111In)-pentetreotide single-photon CT (SPECT).[44, 45, 46]  Nockel et al studied the accuracy of 68Ga–DOTA-(Tyr3)-octreotate (Ga-DOTATATE) PET/CT for localizing insulinoma and suggested that this technique may be considered as an adjunct imaging study when all other imaging studies are negative and when a minimally invasive surgical approach is planned.[8]

Ultrasonography

Endoscopic ultrasonography (EUS) detects 77% of insulinomas in the pancreas.[3, 4, 5] Combining EUS with CT can increase the yield, resulting in the detection and localization of the majority of sporadic insulinomas.

See the image below.

Endoscopic ultrasonography in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV) (Rosch, 1992).

Endoscopic ultrasound–guided fine-needle aspiration biopsy of insulinoma has been described. However, biopsy cannot distinguish benign from malignant insulinoma, and preoperative tissue sampling is usually not necessary.

Insulinomas are solitary tumors in 90% of patients. In MEN 1 syndrome, multiple microinsulinomas and macroinsulinomas are found, although hypoglycemia may be caused by a single tumor. The tumors are distributed evenly throughout the pancreas. Tumor size does not relate to the severity of clinical symptoms. Ectopic insulinomas may be found in the ligament of Treitz.

No histologic criteria are available to distinguish benign from malignant insulinomas. Malignant tumors are usually larger (average size 6.2 cm), and a third of them have metastasized to the liver. Insulinoma tumor cells contain less insulin and secretory granules than normal B cells but higher levels of proinsulin. Atypical granules, or even agranular cells, are frequent. The clinical response to diazoxide and somatostatin correlates with the frequency and type of granules.

No histologic criteria are available to distinguish benign from malignant insulinomas. Malignant tumors are usually larger than benign ones (approximately 4.2 versus 1.8 cm, respectively). Insulinoma tumor cells contain less insulin and secretory granules than normal B cells but higher levels of proinsulin. Atypical granules, or even agranular cells, are frequent. The clinical response to diazoxide and somatostatin correlates with the frequency and type of granules.[47]

A specific tumor-node-metastasis (TNM) staging system has not been validated yet for insulinomas. The American Joint Committee on Cancer (AJCC) staging for well-differentiated neuroendocrine tumors arising in the pancreas is used.[48, 49]

Primary tumor (T):

• TX - Tumor cannot be assessed
• T1 - Tumor limited to the pancreas and < 2 cm in size
• T2 - Tumor limited to the pancreas and 2−4 cm in size
• T3 - Tumor limited to the pancreas and > 4 cm in size; or tumor invading the duodenum or common bile duct
• T4 - Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels (celiac axis or the superior mesenteric artery)

Regional lymph Nodes (N):

• NX - Regional lymph nodes cannot be assessed
• N0 - No regional lymph node involvement
• N1 - Regional lymph node involvement

Distant metastasis (M):

• M0 - No distant metastasis
• M1 - Distant metastases
• M1a - Metastasis confined to liver
• M1b - Metastases in at least one extrahepatic site (eg, lung, ovary, nonregional lymph node, peritoneum, bone)
• M1c - Both hepatic and extrahepatic metastases

AJCC prognostic stage groups are shown in the table below.

Table. AJCC Prognostic Stage Groups (Open Table in a new window)

Medical therapy is indicated in patients with malignant insulinomas and in those who will not or cannot undergo surgery. These measures are designed to prevent hypoglycemia and, in patients with malignant tumors, to reduce the tumor burden. In malignant insulinomas, dietary therapy with frequent oral feedings or enteral feedings may control mild symptoms of hypoglycemia. A trial of glucagon may be attempted to control hypoglycemia.

Diazoxide is related to the thiazide diuretics and reduces insulin secretion. Adverse effects include sodium retention, a tendency to congestive cardiac failure, and hirsutism. Prescribe hydrochlorothiazide to counteract the edema and hyperkalemia secondary to diazoxide and to potentiate its hyperglycemic effect.

Of patients with insulinoma, 50% may benefit from the somatostatin analog octreotide to prevent hypoglycemia.[50] The effect of the therapy depends on the presence of somatostatin receptor subtype 2 on insulinoma tumor cells. Use of the somatostatin analogs lanreotide and pasireotide have also been reported.[2, 51]

An OctreoScan is not a prerequisite before starting octreotide treatment. In patients with insulinoma and a negative scan finding, somatostatin decreased insulin levels significantly and lowered the incidence of hypoglycemic events.[52]  

Indications for chemotherapy include progressive disease with an increase of greater than 25% of the main tumor masses in a follow-up period of 12 months, or tumor symptoms not treatable with other methods. Combination regimens have achieved better results than single agents.

The current medical treatment choices are those used for any metastatic neuroendocrine gastroenteric pancreatic tumor. Options are as follows:

• Combination therapy with 5-fluorouracil (5FU) and either streptozotocin (STZ) or doxorubicin (DOX) has been studied. In a phase II/III trial, 5FU/STZ and 5FU/DOX yielded comparable modest response rates (16% versus 15.9%, respectively) and progression-free survival (5.3 vs 4.5 months); however, median survival was better with 5FU/STZ than with 5FU/DOX (24.3 vs 15.7 months, respectively). Patients were allowed to cross over to dacarbazine after progression and had median survival of 11.9 months.[53]

• Dacarbazine- and temozolomide-based regimens: There appears to be a correlation between expression of methylguanine DNA methyltransferase (MGMT) and temozolomide responsiveness in advanced neuroendocrine tumors. MGMT is an enzyme that is responsible for DNA repair induced by alkylating agent chemotherapy.

• Molecularly targeted therapy: This includes vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib, sorafenib, pazopanib, or cabozantinib.

• Mechanistic (previously mammalian) target of rapamycin (mTOr) inhibitors: Everolimus, with or without octreotide

• Peptide receptor radioligand therapy: Lutetium Lu 177 dotatate (Lutathera)

The mTOR inhibitor everolimus is approved for treatment of locally advanced or metastatic neuroendocrine tumors of pancreatic origin. In a French study, everolimus therapy normalized blood glucose levels in 11 of 12 patients with metastatic insulinoma and refractory hypoglycemia, with the therapeutic effect maintained for a median duration of 6.5 months (range 1-35+ months). However, three patients discontinued everolimus because of cardiac and/or pulmonary adverse events, which led to two deaths.[54]  

Lutetium Lu 177 dotatate, the first peptide receptor radionuclide therapy, was approved by the US Food and Drug Administration in 2018 for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs).[55] It consists of a radioactive isotope (Lu 177) attached to dotatate, a molecule that binds to somatostatin receptors on GEP-NETs; the compound then enters the cells, and beta radiation emitted by Lu-177 helps kill the cells.

Approval was based on two trials. In the NETTER-1 clinical trial, which included 229 patients with metastatic GEP-NETs, the risk  of disease progression or death was 79% lower in patients receiving lutetium Lu 177 dotatate than in those receiving high-dose octreotide long-acting repeatable (LAR). Median progression-free survival was not reached in the Lu 177 arm, compared with 8.5 months for octreotide LAR. An interim overall survival analysis determined that Lu 177 treatment led to a 48% reduction in the estimated risk of death (hazard ratio 0.52, 95% CI: 0.32-0.84) compared with octreotide LAR.[56] The second study, a single-institution, single-arm, open-label trial. reported complete or partial tumor shrinkage in 16% of a subset of 360 patients with GEP-NETs.[55]

Off-label use of other agents has been described in case reports.[57, 58] Pasireotide, a novel multireceptor somatostatin analogue, has been used for treatment of refractory hypoglycemia in malignant insulinoma. The multitargeted receptor tyrosine kinase inhibitor sunitinib has been used; sunitinib has antiangiogenic and antitumor activity, but does not appear to have a direct action on glycemic control, and indeed may worsen hypoglycemia.[58]

Ablation

Ablation is a nonsurgical option that has had some long-term success. CT-guided radiofrequency ablation has been used successfully to treat insulinoma in an elderly patient whose hypoglycemia that was refractory to diazoxide, and who was not a candidate for surgery because of comorbidities and poor physical condition.[59] In addition to radiofrequency ablation, successful results have been attained with embolization and with ethanol, among other techniques.[60, 61]

Because insulinoma resection achieves cure in 90% of patients, it is currently the therapy of choice. Enucleation is the preferred technique.

Preoperative management

Preoperative management is as follows:

• A preoperative trial with diazoxide is indicated to determine whether the patient is a responder (5-10% of patients do not respond).

• Monitor blood glucose level throughout surgery.

• Infuse 10% dextrose in water to maintain an adequate glucose level.

• In patients with multiple endocrine neoplasia type 1 (MEN 1), hypercalcemia must be corrected first by parathyroidectomy before insulinoma resection.[62]

Tumor location

If an open procedure is selected, fully expose the pancreas, including a wide Kocher maneuver to allow complete bimanual palpation.

Compared with open procedures, laparoscopy has been found to permit equivalent oncologic resection of pancreatic neuroendocrine tumors, along with decreased postoperative pain, better cosmetic results, shorter hospital stay, and a shorter postoperative recovery period.[63] A large study from Spain showed laparoscopic surgery to be safe and effective in benign and malignant tumor resection.[9]

Laparoscopic enucleation techniques, also in combination with preservation of the spleen for distal pancreatic tumors, have been described.[64] Because of the small likelihood that a tumor that presents without metastatic spread is malignant, insulinomas may be removed by enucleation.[65] Care should be taken to achieve total tumor capsule removal to prevent tumor recurrence.

If enucleation is not possible, a larger pancreatic resection including pancreaticoduodenectomy may be necessary. This should only rarely be required. When metastatic insulinoma is found on a patient's initial presentation, the organ spread is to liver and sometimes to bone.

Other surgical considerations are as follows:

• Avoid total pancreatectomy because of its high morbidity and mortality rates.

• Major resections, such as the Whipple procedure, may become necessary when the tumor is found in the pancreatic head and local excision is not possible.

• Resect all gross disease when multiple tumors or metastases are present.

• If insulinoma is associated with type 1 multiple endocrine neoplasia (MEN 1), the management strategy is modified because tumors are often multiple, diffusely spread in the pancreas, and of small size. Definite cure by surgery is rare.

• Subtotal pancreatectomy with enucleation of tumors from the pancreatic head and uncinate processus often is recommended over simple enucleation because of frequent multiple tumors in MEN 1.

Metastatic disease

Insulinomas are found to be metastatic at surgery in about 5-10% of patients. It would be extremely uncommon for metastases to develop in a case in which only a solitary lesion was found on initial presentation.

Patients who are responsive to diazoxide should be continued on it while more invasive imaging studies are performed, before repetitive surgery is considered. If the patient is not responsive (5-10%) or if drug intolerance is present and ectopic disease is excluded, a blind distal two-thirds pancreatectomy may be performed. However, this procedure has only a 25% success rate.

Most authorities recommend serial sectioning during resection. Tumors that are not found at surgery normally are located in the pancreatic head (54%), body (20%), and tail (14%).

Even when metastases are found, surgical excision is often feasible before any medical, chemotherapeutic, or other interventional therapy is considered. Resect all gross disease, including wedge resections of hepatic metastases. Avoid ligation of the hepatic artery in case further regional infusion therapy becomes necessary.

Consult with the anesthetist to plan for precise preoperative and intraoperative blood glucose monitoring. The approach should be multidisciplinary, with an endocrinologist, surgeon, and anesthesiologist.

Considerations include the following:

• Because insulin secretion by most insulinomas is not responsive to glucose levels, carbohydrate feedings every 2-3 hours can help maintain euglycemia, although obesity may develop.
• Glucagon should be available for emergency use.
• Exercise may aggravate hypoglycemia in patients with insulinoma.

Guidelines contributor: Evan S Ong, MD, MS Assistant Professor of Surgery, Section of Surgical Oncology, University of Arizona College of Medicine

The following organizations have issued clinical guidelines for the management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs):

• National Comprehensive Cancer Network (NCCN)
• North American Neuroendocrine Tumor Society (NANETS)
• European Neuroendocrine Tumor Society (ENETS)
• European Society for Medical Oncology (ESM0)

Grading and Staging

Grading schemes for neuroendocrine tumors (NETs) use mitotic count; the level of the nuclear protein Ki-67, which is associated with cellular proliferation; and assessment of necrosis. The World Health Organization (WHO) and the European Neuroendocrine Tumor Society (ENETS)  both incorporate mitotic count and Ki-67 proliferation for the classification of gastroenteropancreatic NETs (GEP-NETs).[66, 67, 68]

Tumors fall into one of the following three grades[69] :

• G1: Mitotic count < 2/2 mm ² (10 high-power fields); Ki-67 index < 3%
• G2: Mitotic count < 2-20/2 mm ²; Ki-67 index 3-20%
• G3: Mitotic count > 20/2 mm ²; Ki-67 index > 20%

G1 and G2 NETs are well differentiated; as a rule, G3 NETs are poorly differentiated, but rarely may be well differentiated.[48]

The National Comprehensive Cancer Network (NCCN) recommends that tumor differentiation, mitotic rate, and Ki-67 rate be included in the pathology report and that the specific classification and grading scheme be noted to avoid confusion. Clinicians are advised to view histologic grade as a general guide and use clinical judgment to make treatment decisions, particularly in cases of discordance between differentiation and Ki-67 proliferation results.[48]

NCCN guidelines recommend staging according to the 8th edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual.[49]

For staging of GEP-NETs, the European Society for Medical Oncology (ESMO) guidelines, updated in 2020, utilize the tumor-node-metastasis (TNM) classification created by the ENETS and the 2019 WHO grading system.[69]

In 2013, the North American Neuroendocrine Tumor Society (NANETS) concluded that while the criteria differ among the various classification systems, the underlying data are similar and pathology reports should include notation of the systems and parameters used to assign the grade and stage.[70]

For the evaluation of insulinoma, National Comprehensive Cancer Network guidelines recommend abdominal multiphasic CT or MRI and measurement of serum insulin, pro-insulin, and C-peptide levels during concurrent hypoglycemia. The following studies may also be performed, as appropriate[48] :

• Endoscopic ultrasound (EUS)
• Other biochemical evaluation as clinically indicated 
• Somatostatin receptor–based imaging;  ⁶⁸Ga-dotatate imaging preferred (PET/CT or PET/MRI) or somatostatin receptor scintigraphy
• Chest CT ± contrast
• Consider testing for inherited genetic syndromes

European Neuroendocrine Tumor Society guidelines note that "the exact criteria for the diagnosis of insulinoma continue to evolve and vary in different consensus documents and reviews", but cite proposed diagnostic criteria from a consensus report from the US Endocrine Society, which include endogenous hyperinsulinism documented by symptoms, signs, or both, and plasma findings as follows[16] :

• Glucose < 55 mg/dl (3.0 mmol/L)
• Insulin ≥3.0 μU/ml (18 pmol/L)
• C-peptide ≥0.6 ng/ml (0.2 nmol/L)
• Proinsulin ≥5.0 pmol/L

Evaluation of serum chromogranin A (CgA) levels are frequently not helpful for diagnosing insulinoma, as an elevated CgA value has only a 73% specificity, compared with 92% specificity for non-insulinoma pancreatic NETs.[16]

National Comprehensive Cancer Network (NCCN) guidelines recommend resection as the primary treatment for most localized pancreatic neuroendocrine tumors (NETs). Exceptions include patients with life-limiting comorbidities or high surgical risk. In addition, observation may be appropriate for incidentally discovered tumors < 1 cm, depending on the site.[48]

Prior to surgery, NCCN recommends that symptoms of hormonal excess be treated with octreotide or lanreotide; however, such treatment is contraindicated in patients with insulinoma because of the potential for fatal complications. Specific recommendations vary by tumor subtype.Cholecystectomy is recommended during surgical resection if treatment with octreotide or lanreotide is planned, due to the increased rate of biliary problems associated with long-term use of these agents.[48]

Additional NCCN recommendations for insulinoma treatment include the following[48] :

• Stabilize glucose levels with diet and/or diazoxide; everolimus may be considered

• Primary treatment is enucleation; consider laparoscopic resection for solitary tumors

• Deeper or invasive tumors or those with proximity to the main pancreatic duct require pancreatoduodenectomy if located in the head and laparoscopic distal pancreatectomy if in a distal location, with preservation of the spleen for smaller tumors

European Neuroendocrine Tumor Society guidelines include the following minimal consensus statements on treatment of insulinomas[16] :

• Surgery remains the preferred treatment whenever possible, but medical treatment is needed prior to surgery, in recurrent cases, and in malignant insulinomas.
• In additional to diazoxide, frequent small meals, somatostatin analogs, and the mTOR inhibitor everolimus has been effective in controlling hypoglycemia; sunitinib also has been effective in a few patients. In malignant insulinomas, peptide receptor–targeted radiotherapy (PRRT) or chemoembolization can help control the hypoglycemia.
• Surgical exploration for possible cure should be performed in all patients with insulinomas if non-resectable metastatic disease is not present, with or without MEN1.
• A laparoscopic approach is generally recommended in patients with sporadic disease with imaged tumors.
• In the uncommon patient who is not thought to be a surgical candidate, successful treatment of localized insulinomas with ablative therapy, either endoscopically directed or percutaneously with radiologic direction, has been reported but further data are required. Successful use of EUS-directed ablation using ethanol injection or CT-guided radiofrequency ablation has also been reported.

Diazoxide is the drug of choice because it inhibits insulin release from the tumor. Adverse effects must be treated with hydrochlorothiazide. In patients not responsive to or intolerant of diazoxide (10%), a somatostatin analog may be indicated to prevent hypoglycemia.

Experience with systemic chemotherapy is limited. The traditional regimen of choice has been streptozocin and doxorubicin. Response rates as high as 69% have been reported but radiologic response is lower and due to uncertainty about efficacy and increased toxicity, this regimen is not accepted as a standard first-line therapy.

Class Summary

Inhibit insulin release from the tumor.

Diazoxide (Proglycem, Hyperstat)

Produces an increase in blood glucose within 1 h by inhibition of insulin release from the insulinoma.

Class Summary

Used to counteract edema and hyperkalemia secondary to diazoxide and to potentiate its hyperglycemic effect.

Hydrochlorothiazide (Microzide, HydroDIURIL, Esidrix)

Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water as well as potassium and hydrogen ions.

Class Summary

May control symptoms by suppressing secretion of gastroenteropancreatic peptides including insulin. High-dose treatment also may lead to additional antiproliferative effects. However, long-term application of somatostatin may down-regulate receptor expression levels, resulting in decreased efficiency despite increasing doses. Both short- and long-acting depot preparations are available.

Lanreotide (Somatuline Depot)

Long-acting analog of somatostatin, administered q4wk.

Octreotide acetate (Sandostatin)

Acts similarly to the natural hormone somatostatin and can suppress secretion of gastroenteropancreatic peptides, including insulin.

Class Summary

Lutetium Lu 177-dotatate (Lu 177) is a radiolabeled somatostatin analog.

Lutetium Lu 177-dotatate (Lutathera)

Binds to somatostatin receptors, with highest affinity for subtype 2 receptors (SSRT2). Upon binding to somatostatin receptor-expressing cells, including malignant somatostatin receptor–positive tumors, the compound is internalized. Beta emission from Lu 177 induces cellular damage by forming free radicals in somatostatin receptor-positive cells and in neighboring cells. It is indicated for somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.

Class Summary

These agents inhibit cell growth and proliferation.

Streptozocin (Zanosar)

Has high affinity for neuroendocrine cells, inhibits cell proliferation, and is cytolytic. Interferes with normal function of DNA by alkylation and protein modification.

Temozolomide (Temodar)

Orally active alkylating agent; may be considered in the treatment of metastatic pancreatic neuroendocrine tumors. 

Class Summary

Mammalian target of rapamycin (mTOr), a serine-threonine kinase is dysregulated in several human cancers. Inhibitors of mTOR reduces cell proliferation, angiogenesis, and glucose uptake.

Everolimus (Afinitor)

Everolimus is indicated for progressive neuroendocrine tumors (PNET) located in the pancreas that are not surgically resectable or are metastatic. It is also indicated for well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung.

After insulinoma resection, hyperglycemia may persist for 48-72 hours because of chronic down-regulation of insulin-receptors by the previously high circulating insulin levels secreted by the tumor and the suppression of normal pancreatic B cells. Small subcutaneous doses of insulin every 3-6 hours may be necessary if plasma glucose level exceeds 300 mg/dL (16.7 mmol/L).

Patients with major pancreatic resections may develop diabetes mellitus.

Streptozocin chemotherapy appears to be toxic to cells that produce insulin. For insulinomas, some cases of sustained improvement in hypoglycemic attacks have been reported, particularly when streptozotocin has been used.

Short-acting somatostatin analogues may be tried to control insulin release. In patients with unresectable metastatic disease to the liver, when systemic chemotherapy was unsuccessful, embolization of the hepatic artery and intraarterial chemotherapy may be indicated to control symptoms and hormone release, to inhibit tumor growth, and to improve survival.[71]

Continue diazoxide and hydrochlorothiazide in patients who are not fit for surgery or when tumor resection was unsuccessful.

In advanced metastatic disease, the indications for chemotherapy or other interventional treatments must be emphasized in a multidisciplinary way and discussed with surgeons, specialists in chemoembolization, gastroenterologists, endocrinologists, and medical oncologists.

See the list below:

• Surgical complications (eg, pancreatic leakage) occur in about 5% of patients; the surgical complication rate has improved significantly in recent years.
• Pseudocysts
• Pancreatitis
• Abscess
• Other complications include intestinal obstruction, pleural effusion, hemorrhage, and fistula formation
• Permanent diabetes mellitus may occur in about 5% of patients, mainly in those who undergo major pancreatic resections

Approximately 90-95% of insulinomas are benign. Long-term cure with complete resolution of preoperative symptoms is expected after complete resection.

Recurrence of benign insulinomas was observed in 5.4% of patients in a series of 120 patients over a period of 4-17 years. The same diagnostic and therapeutic approach was recommended, including surgical exploration and tumor resection.[72]

Patients may develop nonfunctioning metastatic disease to the liver up to 14 years after insulinoma resection.[73] Note that some insulinomas are indolent (depending on the tumor biology), resulting in prolonged survival.