Insulinoma

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Practice Essentials

Insulinomas are the most common cause of hypoglycemia resulting from endogenous hyperinsulinism. Approximately 90-95% of insulinomas are benign, and long-term cure with total resolution of preoperative symptoms is expected after complete resection.[1, 2] See the image below.



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CT scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is....

Signs and symptoms

Insulinomas are characterized clinically by the Whipple triad, as follows:

About 85% of patients with insulinoma present with one of the following symptoms of hypoglycemia:

Hypoglycemia can also result in the following:

See Presentation for more detail.

Diagnosis

Lab studies

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.

The biochemical diagnosis of insulinoma is established in 95% of patients during prolonged fasting (up to 72 h) when the following results are found:

Approximately 5% of patients with insulinomas will show postprandial but not fasting hypoglycemia, and in those cases the diagnosis can be established by laboratory testing performed after the patient consumes a standardized meal.[3]

Imaging studies

Insulinomas can be located with the following imaging modalities:

See Workup for more detail.

Management

Pharmacologic therapy

Pharmacologic treatment is designed to prevent hypoglycemia and, in patients with malignant tumors, to reduce the tumor burden. Agents used in this therapy include the following:

Surgery:

Ablation:

See Treatment and Medication for more detail.

Background

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%).[12]

In 1927, Wilder established the association between hyperinsulinism and a functional islet cell tumor.[13] 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.

Pathophysiology

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 (MEN1). Overall, insulinomas are associated with MEN1 in 5% of patients. On the other hand, 21% of patients with MEN1 develop insulinomas. Because of the association of insulinomas with MEN1, consideration should be given to screening family members of insulinoma patients for MEN1.[14]

An in vitro study by Henquin et al identified three distinct patterns of insulin secretion by insulinomas, as follows[15] :

Increased expression of the phosphorylated mechanistic target of rapamycin (mTOR) signaling pathway and its downstream serine/threonine kinase p70S6k has been observed in insulinoma tumor specimens.[16] This discovery led to studies that established the mTOR inhibitor everolimus as a therapeutic option in insulinoma.[17]

Etiology

The genetic changes in neuroendocrine tumors are under investigation.[18] 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.[19]

One study showed k-ras mutation to be present in 23% of insulinomas.[18] Another study found T372R mutations in the YY1 gene in 30% of sporadic insulinomas.[20]

Most metastatic insulinomas appear to derive from non-functional pancreatic neuroendocrine tumors. However, a few metastatic insulinomas may derive from non-metastatic insulinomas.[21]

Epidemiology

United States

Insulinomas are the most common functional pancreatic endocrine tumors, comprising 55% of such cases. The incidence is 1-32 cases per million persons per year.[22]

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.[23] 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.[10] These reports may be an underestimate.

Mortality/Morbidity

Pancreatic fistula is the most common major complication of surgery for insulinoma,[24]  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.[25] The median survival in patients with metastatic disease to the liver ranges from 16-26 months.

Race-, Sex-, and Age-related Demographics

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.[11] In insulinoma patients with MEN1, however, more cases are reported in men than in women, and the median age at diagnosis is younger, at 38 years.[11, 26]

Prognosis

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.[27]

Patients may develop nonfunctioning metastatic disease to the liver up to 14 years after insulinoma resection.[28] Note that some insulinomas are indolent (depending on the tumor biology), resulting in prolonged survival.

History and Physical Examination

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

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

Approach Considerations

The classic hallmark of insulinomas is the Whipple triad, which consists of the following:[24]

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 elevated levels of the following during a supervised fast:

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

Laboratory Studies

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 falls to 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.[24]

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.[40]

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

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

Approximately 5% of patients with insulinomas do not have fasting hypoglycemia, but do have postprandial hypoglycemia. In those cases, the diagnosis can be established with laboratory testing at baseline (including assays for insulin antibodies and oral hypoglycemic agents, if not previously performed) and then every 30 minutes after administering a standardized non-liquid meal (typically breakfast) that is – by the history – associated with hypoglycemic symptoms. Testing is continued until symptomatic hypoglycemia occurs, or maximally for 5 hours.[3]

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 (MEN1) must be evaluated by excluding the following:

Imaging Studies

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.[42] 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.[43] 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.[44] See the image below.



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CT scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is....

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.[45]

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.[7]

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.[8]

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.[46, 47] 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.[48] Luo et al reported that PET/CT scanning with gallium-68 (68Ga)-NOTA–exendin-4 correctly detected insulinomas in 42 of 43 patients.[49]

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).[50, 51, 52]  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.[9]

Ultrasonography

Endoscopic ultrasonography (EUS) detects 77% of insulinomas in the pancreas.[4, 5, 6] Combining EUS with CT can increase the yield, resulting in the detection and localization of the majority of sporadic insulinomas.

See the image below.



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Endoscopic ultrasonography in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splen....

Other Tests

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.

 

Histologic Findings

Insulinomas are solitary tumors in 90% of patients. In MEN1 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.

Case reports describe ectopic insulinomas in a variety of locations outside the pancreas.[53]

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.[54]

Staging

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.[55, 56]

Primary tumor (T):

Regional lymph Nodes (N):

Distant metastasis (M):

AJCC prognostic stage groups are shown in the table below.

Table. AJCC Prognostic Stage Groups



View Table

See Table

Medical Care

Medical therapy is indicated in patients with malignant insulinomas and in those who will not or cannot undergo surgery, and may be used to control symptoms in patients who are awaiting 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 (SSA) octreotide to prevent hypoglycemia.[57] The effect of the therapy depends on the presence of somatostatin receptor subtype 2 on insulinoma tumor cells. Because SSAs can produce paradoxical aggravation of hypoglycemia, an initial trial of short-acting octreotide with close monitoring of glucose levels is advisable; once it confirms a positive effect on glucose levels, the patient can be switched to a long-acting formulation.[3]

Use of the SSAs lanreotide and pasireotide have also been reported.[2, 58]  Pasireotide, a second-generation SSA, is not approved for this indication, but case reports describe efficacy in patients with metastatic insulinoma and hypoglycemia refractory to first-generation SSAs.[59]

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.[60]  

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:

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.[62]  

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).[63] 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.[64] 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.[63]

Off-label use of other agents has been described in case reports.[65, 66]   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.[66]

In patients with unresectable liver metastases unresponsive to systemic chemotherapy, embolization of the hepatic artery and intra-arterial chemotherapy may be indicated to control symptoms and hormone release, to inhibit tumor growth, and to improve survival.[67]

Surgical Care

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:

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.[69] A large study from Spain showed laparoscopic surgery to be safe and effective in benign and malignant tumor resection.[10]

Laparoscopic enucleation techniques, also in combination with preservation of the spleen for distal pancreatic tumors, have been described.[70] Because of the small likelihood that a tumor that presents without metastatic spread is malignant, insulinomas may be removed by enucleation.[71] 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:

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.

Postoperative care

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 the plasma glucose level exceeds 300 mg/dL (16.7 mmol/L).

Ablation

Ablation is a nonsurgical option that is increasingly performed for small (< 2 cm) insulinomas, especially in patients considered unfit for surgery.[72, 73, 74, 3] A multi-institutional study comprising 178 patients concluded that endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) of insulinoma is safer than surgical resection and is highly effective.[74] Adverse events occurred in 18.0% of patients in the EUS-RFA arm versus 61.8% in the surgery arm; no severe adverse events were observed in the EUS-RFA group compared with 15.7% after surgery (P < .0001 for both results).

Clinical efficacy was 100% after surgery and 95.5% after EUS-RFA (P = .160). Hospital stay was significantly longer in the surgical group (11.1 ± 9.7 vs 3.0 ± 2.5 days). Fifteen lesions (16.9%) recurred after EUS-RFA and underwent a successful repeat EUS-RFA  or surgical resection.[74]

In addition to radiofrequency ablation, successful results have been attained with embolization and with ethanol, among other techniques.[75, 76, 77]

Consultations

Surgery for insulinoma requires consultation with the anesthetist to plan for precise preoperative and intraoperative blood glucose monitoring. The approach should be multidisciplinary, with an endocrinologist, surgeon, and anesthesiologist. In advanced metastatic disease, chemotherapy or other interventional treatments should be managed by a multidisciplinary team that includes surgeons, specialists in chemoembolization, gastroenterologists, endocrinologists, and medical oncologists.

Complications

See the list below:

Diet and Activity

Considerations include the following:

Guidelines Summary

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):

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).[78, 79, 80]

Tumors fall into one of the following three grades[81] :

G1 and G2 NETs are well differentiated; as a rule, G3 NETs are poorly differentiated, but rarely may be well differentiated.[55]

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.[55]

NCCN guidelines recommend staging according to the 8th edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual.[56]

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.[81]

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.[82]

Diagnosis

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[55] :

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[22] :

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.[22]

Treatment

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.[55]

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.[55]

Additional NCCN recommendations for insulinoma treatment include the following[55] :

European Neuroendocrine Tumor Society guidelines include the following recommendations on treatment of insulinomas[22] :

Medication Summary

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.

Diazoxide (Proglycem, Hyperstat)

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

Class Summary

Inhibit insulin release from the tumor.

Hydrochlorothiazide (Microzide, HydroDIURIL, Esidrix)

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

Class Summary

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

Lanreotide (Somatuline Depot)

Clinical Context:  Long-acting analog of somatostatin, administered q4wk.

Octreotide acetate (Sandostatin)

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

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.

Lutetium Lu 177-dotatate (Lutathera)

Clinical Context:  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

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

Streptozocin (Zanosar)

Clinical Context:  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)

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

Class Summary

These agents inhibit cell growth and proliferation.

Everolimus (Afinitor)

Clinical Context:  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.

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.

Further Inpatient Care

 

 

 

 

What are insulinomas?How are insulinomas clinically characterized?What are symptoms of hypoglycemia in patients with insulinoma?What causes hypoglycemia in patients with insulinoma?What is the hallmark of an insulinoma?How is a biochemical diagnosis of insulinoma established?Which imaging modalities are used in the diagnosis of insulinomas?Which medications are used in the treatment of insulinoma?What are the surgical options for treatment of insulinoma?What are insulinomas?What is the pathophysiology of insulinoma?What are patterns of insulin secretion by insulinomas?What is the incidence of insulinoma in the US?What is the global incidence of insulinoma?What is the mortality and morbidity associated to insulinoma?What are the racial predilections in the prevalence of insulinoma?What are the sexual predilections in the prevalence of insulinoma?Which age groups have the highest incidence of insulinoma?Which clinical history findings are characteristic of insulinoma?What causes insulinoma?How is insulinoma differentiated from other causes of hypoglycemia?What is the classic hallmark of insulinomas?What are the diagnostic criteria for insulinoma?What is the role of lab testing in the diagnosis of insulinoma?How is a biochemical diagnosis of insulinoma made?How is multiple endocrine neoplasia type 1 (MEN 1) assessed during the evaluation for insulinoma?What is the role of imaging studies in the diagnosis of insulinoma?What is the role of CT scanning and MRI in the diagnosis of insulinoma?What is the role of arteriography in the diagnosis of insulinoma?What is the role of nuclear medicine in the diagnosis of insulinoma?What is the role of ultrasonography in the diagnosis of insulinoma?What is the role of portal venous sampling in the evaluation of insulinoma?What is the role of anti-insulin labeled with iodine-131 in the evaluation of insulinoma?What is the role of biopsy in the evaluation of insulinoma?Which histologic findings are characteristic of insulinoma?How is insulinoma staged?What are the medical treatment options for insulinoma?What are the medical treatment options for metastatic insulinoma?How is refractory hypoglycemia treated in patients with insulinoma?What is the role of ablation in the treatment of insulinoma?What is the treatment of choice for insulinoma?What is included in preoperative management of insulinoma?What are the surgical options for the treatment of insulinoma?What is the role of surgery in the treatment of metastatic insulinoma?Which specialist consultations are beneficial for patients with insulinoma?Which diet and activity modifications are used in the treatment of insulinoma?Which organizations have issued clinical treatment guidelines for insulinoma?What are grading schemes for insulinoma?What are the NCCN guidelines for grading and staging insulinoma?What the ESMO and NANETS guidelines for grading and staging of insulinoma?What are the diagnostic guidelines for insulinoma?What are the guidelines for treatment of insulinoma?What is the role of diazoxide in the treatment of insulinoma?Which medications in the drug class Antineoplastic, mTOr Kinase Inhibitor are used in the treatment of Insulinoma?Which medications in the drug class Antineoplastic Agents are used in the treatment of Insulinoma?Which medications in the drug class Radiopharmaceuticals are used in the treatment of Insulinoma?Which medications in the drug class Somatostatin Analogs are used in the treatment of Insulinoma?Which medications in the drug class Diuretics are used in the treatment of Insulinoma?Which medications in the drug class Hyperglycemic agents are used in the treatment of Insulinoma?What is included in inpatient care for insulinoma?What are the indications for discontinuation of diazoxide and hydrochlorothiazide in the treatment of insulinoma?Which specialists should be included in a multidisciplinary treatment team for the management of insulinoma?What are complications of insulinoma?What is the prognosis of insulinoma?

Author

Zonera Ashraf Ali, MBBS, Consulting Staff, Main Line Oncology Hematology Associates, Lankenau Cancer Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Lawrence T Kim, MD, FACS, FACE, Professor, Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, University of North Carolina at Chapel Hill School of Medicine; Member, UNC Lineberger Comprehensive Cancer Center

Disclosure: Nothing to disclose.

Additional Contributors

Pradyumna D Phatak, MBBS, MD, Chair, Division of Hematology and Medical Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell Park Cancer Institute

Disclosure: Received honoraria from Novartis for speaking and teaching.

Acknowledgements

Klaus Radebold, MD, PhD Former Research Associate, Department of Surgery, Yale University School of Medicine

Disclosure: Nothing to disclose.

References

  1. Zhuo F, Anastasopoulou C. Insulinoma. 2024 Jan. [View Abstract]
  2. de Herder WW, Hofland J. Insulinoma. April 4, 2023. [View Abstract]
  3. [Guideline] Hofland J, Falconi M, Christ E, Castaño JP, Faggiano A, Lamarca A, et al. European Neuroendocrine Tumor Society 2023 guidance paper for functioning pancreatic neuroendocrine tumour syndromes. J Neuroendocrinol. 2023 Aug. 35 (8):e13318. [View Abstract]
  4. Kirkeby H, Vilmann P, Burcharth F. Insulinoma diagnosed by endoscopic ultrasonography-guided biopsy. J Laparoendosc Adv Surg Tech A. 1999 Jun. 9(3):295-8. [View Abstract]
  5. Proye C, Malvaux P, Pattou F, et al. Noninvasive imaging of insulinomas and gastrinomas with endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery. 1998 Dec. 124(6):1134-43; discussion 1143-4. [View Abstract]
  6. McLean A. Endoscopic ultrasound in the detection of pancreatic islet cell tumours. Cancer Imaging. 2004 Mar 29. 4(2):84-91. [View Abstract]
  7. Zhu L, Xue H, Sun Z, Li P, Qian T, Xing X, et al. Prospective comparison of biphasic contrast-enhanced CT, volume perfusion CT, and 3 Tesla MRI with diffusion-weighted imaging for insulinoma detection. J Magn Reson Imaging. 2017 Apr 17. [View Abstract]
  8. Zhao K, Patel N, Kulkarni K, Gross JS, Taslakian B. Essentials of Insulinoma Localization with Selective Arterial Calcium Stimulation and Hepatic Venous Sampling. J Clin Med. 2020 Sep 25. 9 (10):[View Abstract]
  9. Nockel P, Babic B, Millo C, Herscovitch P, Patel D, Nilubol N, et al. Localization of Insulinoma Using 68Ga-DOTATATE PET/CT Scan. J Clin Endocrinol Metab. 2017 Jan 1. 102 (1):195-199. [View Abstract]
  10. Fernandez-Cruz L, Blanco L, Cosa R, Rendon H. Is laparoscopic resection adequate in patients with neuroendocrine pancreatic tumors?. World J Surg. 2008 May. 32(5):904-17. [View Abstract]
  11. Crippa S, Zerbi A, Boninsegna L, Capitanio V, Partelli S, Balzano G, et al. Surgical management of insulinomas: short- and long-term outcomes after enucleations and pancreatic resections. Arch Surg. 2012 Mar. 147 (3):261-6. [View Abstract]
  12. Phan GQ, Yeo CJ, Hruban RH, et al. Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients. J Gastrointest Surg. 1998 Sep-Oct. 2(5):472-82. [View Abstract]
  13. Mathur A, Gorden P, Libutti SK. Insulinoma. Surg Clin North Am. 2009 Oct. 89(5):1105-21. [View Abstract]
  14. Service FJ, McMahon MM, O'Brien PC, Ballard DJ. Functioning insulinoma--incidence, recurrence, and long-term survival of patients: a 60-year study. Mayo Clin Proc. 1991 Jul. 66 (7):711-9. [View Abstract]
  15. Henquin JC, Nenquin M, Guiot Y, Rahier J, Sempoux C. Human Insulinomas Show Distinct Patterns of Insulin Secretion In Vitro. Diabetes. 2015 Oct. 64 (10):3543-53. [View Abstract]
  16. Zhan HX, Cong L, Zhao YP, Zhang TP, Chen G, Zhou L, et al. Activated mTOR/P70S6K signaling pathway is involved in insulinoma tumorigenesis. J Surg Oncol. 2012 Dec. 106(8):972-80. [View Abstract]
  17. Bernard V, Lombard-Bohas C, Taquet MC, Caroli-Bosc FX, Ruszniewski P, Niccoli P, et al. Efficacy of everolimus in patients with metastatic insulinoma and refractory hypoglycemia. Eur J Endocrinol. 2013 May. 168 (5):665-74. [View Abstract]
  18. Hrascan R, Pecina-Slaus N, Martic TN, Colic JF, Gall-Troselj K, Pavelic K. Analysis of selected genes in neuroendocrine tumours: insulinomas and phaeochromocytomas. J Neuroendocrinol. 2008 Aug. 20(8):1015-22. [View Abstract]
  19. Bhatti TR, Ganapathy K, Huppmann AR, Conlin L, Boodhansingh KE, MacMullen C, et al. Histologic and Molecular Profile of Pediatric Insulinomas: Evidence of a Paternal Parent-of-Origin Effect. J Clin Endocrinol Metab. 2016 Jan 12. 161 (3):jc20152914. [View Abstract]
  20. Cao Y, Gao Z, Li L, Jiang X, Shan A, Cai J, et al. Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1. Nat Commun. 2013. 4:2810. [View Abstract]
  21. Zhang J, Jiang R, Hong X, Wu H, Han X, Wu W. Metastatic insulinoma: exploration from clinicopathological signatures and genetic characteristics. Front Oncol. 2023. 13:1109330. [View Abstract]
  22. [Guideline] Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M, et al. ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology. 2016. 103 (2):153-71. [View Abstract]
  23. Larijani B, Aghakhani S, Lor SS, Farzaneh Z, Pajouhi M, Bastanhagh MH. Insulinoma in Iran: a 20-year review. Ann Saudi Med. 2005 Nov-Dec. 25(6):477-80. [View Abstract]
  24. Shin JJ, Gorden P, Libutti SK. Insulinoma: pathophysiology, localization and management. Future Oncol. 2010 Feb. 6 (2):229-37. [View Abstract]
  25. Mehrabi A, Fischer L, Hafezi M, Dirlewanger A, Grenacher L, Diener MK, et al. A systematic review of localization, surgical treatment options, and outcome of insulinoma. Pancreas. 2014 Jul. 43 (5):675-86. [View Abstract]
  26. Sada A, Habermann EB, Szabo Yamashita T, Thompson GB, Lyden ML, Foster TR, et al. Comparison Between Sporadic and Multiple Endocrine Neoplasia Type 1-Associated Insulinoma. J Am Coll Surg. 2022 Nov 1. 235 (5):756-763. [View Abstract]
  27. Rushakoff RJ, Siperstein A, Clark OH. Insulinoma and other Hypoglycemias. January 1, 2009. [View Abstract]
  28. Gonzalez-Gonzalez A, Recio-Cordova JM. Liver metastases 9 years after removal of a malignant insulinoma which was initially considered benign. JOP. 2006. 7(2):226-9.
  29. Dizon AM, Kowalyk S, Hoogwerf BJ. Neuroglycopenic and other symptoms in patients with insulinomas. Am J Med. 1999 Mar. 106(3):307-10. [View Abstract]
  30. Schmitt J, Boullu-Sanchis S, Moreau F, Drui S, Louis B, Chabrier G, et al. Association of malignant insulinoma and type 2 diabetes mellitus: a case report. Ann Endocrinol (Paris). 2008 Feb. 69(1):69-72. [View Abstract]
  31. Ruby RJ, Armato JP, Pyke C, Peters AL. GLP-1 provoked severe hypoglycemia in an individual with type 2 diabetes and a benign insulinoma. Diabetes Care. 2014 Aug. 37 (8):e177-8. [View Abstract]
  32. Awad DH, Gokarakonda SB, Ilahi M. Factitious Hypoglycemia. 2024 Jan. 12(2):133-6. [View Abstract]
  33. Redmon JB, Nuttall FQ. Autoimmune hypoglycemia. Endocrinol Metab Clin North Am. 1999 Sep. 28(3):603-18, vii. [View Abstract]
  34. Eriguchi N, Aoyagi S, Hara M, et al. Nesidioblastosis with hyperinsulinemic hypoglycemia in adults: report of two cases. Surg Today. 1999. 29(4):361-3. [View Abstract]
  35. Malik S, Mitchell JE, Steffen K, Engel S, Wiisanen R, Garcia L, et al. Recognition and management of hyperinsulinemic hypoglycemia after bariatric surgery. Obes Res Clin Pract. 2016 Jan-Feb. 10 (1):1-14. [View Abstract]
  36. Dardano A, Daniele G, Lupi R, Napoli N, Campani D, Boggi U, et al. Nesidioblastosis and Insulinoma: A Rare Coexistence and a Therapeutic Challenge. Front Endocrinol (Lausanne). 2020. 11:10. [View Abstract]
  37. Starke A, Saddig C, Kirch B, Tschahargane C, Goretzki P. Islet hyperplasia in adults: challenge to preoperatively diagnose non-insulinoma pancreatogenic hypoglycemia syndrome. World J Surg. 2006 May. 30(5):670-9. [View Abstract]
  38. Seckl MJ, Mulholland PJ, Bishop AE, Teale JD, Hales CN, Glaser M, et al. Hypoglycemia due to an insulin-secreting small-cell carcinoma of the cervix. N Engl J Med. 1999 Sep 2. 341 (10):733-6. [View Abstract]
  39. Assan R, Perronne C, Assan D, Chotard L, Mayaud C, Matheron S, et al. Pentamidine-induced derangements of glucose homeostasis. Determinant roles of renal failure and drug accumulation. A study of 128 patients. Diabetes Care. 1995 Jan. 18 (1):47-55. [View Abstract]
  40. van Bon AC, Benhadi N, Endert E, Fliers E, Wiersinga WM. Evaluation of endocrine tests. D: the prolonged fasting test for insulinoma. Neth J Med. 2009 Jul-Aug. 67(7):274-8. [View Abstract]
  41. Guettier JM, Lungu A, Goodling A, Cochran C, Gorden P. The Role of Proinsulin and Insulin in the Diagnosis of Insulinoma: A Critical Evaluation of the Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2013 Sep 30. [View Abstract]
  42. Boukhman MP, Karam JM, Shaver J, et al. Localization of insulinomas. Arch Surg. 1999 Aug. 134(8):818-22; discussion 822-3. [View Abstract]
  43. Hashimoto LA, Walsh RM. Preoperative localization of insulinomas is not necessary. J Am Coll Surg. 1999 Oct. 189(4):368-73. [View Abstract]
  44. Liu Y, Song Q, Jin HT, Lin XZ, Chen KM. The value of multidetector-row CT in the preoperative detection of pancreatic insulinomas. Radiol Med. 2009 Sep 30. [View Abstract]
  45. Zhu L, Xue H, Sun H, Wang X, Wu W, Jin Z, et al. Insulinoma Detection With MDCT: Is There a Role for Whole-Pancreas Perfusion?. AJR Am J Roentgenol. 2017 Feb. 208 (2):306-314. [View Abstract]
  46. Hubalewska-Dydejczyk A, Sowa-Staszczak A, Tomaszuk M, Stefańska A. GLP-1 and exendin-4 for imaging endocrine pancreas. A review. Labelled glucagon-like peptide-1 analogues: past, present and future. Q J Nucl Med Mol Imaging. 2015 Jun. 59 (2):152-60. [View Abstract]
  47. Sowa-Staszczak A, Trofimiuk-Müldner M, Stefańska A, Tomaszuk M, Buziak-Bereza M, Gilis-Januszewska A, et al. 99mTc Labeled Glucagon-Like Peptide-1-Analogue (99mTc-GLP1) Scintigraphy in the Management of Patients with Occult Insulinoma. PLoS One. 2016. 11 (8):e0160714. [View Abstract]
  48. Christ E, Wild D, Forrer F, Brändle M, Sahli R, Clerici T, et al. Glucagon-Like Peptide-1 Receptor Imaging for Localization of Insulinomas. J Clin Endocrinol Metab. 2009 Oct 9. [View Abstract]
  49. Luo Y, Pan Q, Shao Y, Yu M, Wu W, Xue H, et al. Glucagon-like Peptide-1 Receptor PET/CT with 68Ga-NOTA-exendin-4 for Detecting Localized Insulinoma: a Prospective Cohort Study. J Nucl Med. 2016 Jan 21. [View Abstract]
  50. Wild D, Christ E, Caplin ME, et al. Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. J Nucl Med. 2011 Jul. 52(7):1073-8. [View Abstract]
  51. Christ E, Antwi K, Fani M, Wild D. Innovative imaging of insulinoma: the end of sampling? A review. Endocr Relat Cancer. 2020 Jan 1. [View Abstract]
  52. Schillaci O, Massa R, Scopinaro F. 111In-pentetreotide scintigraphy in the detection of insulinomas: importance of SPECT imaging. J Nucl Med. 2000 Mar. 41 (3):459-62. [View Abstract]
  53. Guerrero-Pérez F, Vilarrasa N, Huánuco LV, Busquets J, Secanella L, Vercher-Conejero JL, et al. Ectopic insulinoma: a systematic review. Rev Endocr Metab Disord. 2023 Dec. 24 (6):1135-1146. [View Abstract]
  54. Berger M, Bordi C, Cüppers HJ, Berchtold P, Gries FA, Münterfering H, et al. Functional and morphologic characterization of human insulinomas. Diabetes. 1983 Oct. 32 (10):921-31. [View Abstract]
  55. [Guideline] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and Adrenal Tumors. NCCN. Available at http://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Version 1.2023 — August 2, 2023; Accessed: March 4, 2024.
  56. American Joint Committee on Cancer. Neuroendocrine Tumors of the Pancreas. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, et al, eds. AJCC Cancer Staging Manual. 8th Ed. Chicago: American College of Surgeons; 2017. 407-22.
  57. Arnold R, Simon B, Wied M. Treatment of neuroendocrine GEP tumours with somatostatin analogues: a review. Digestion. 2000. 62 Suppl 1:84-91. [View Abstract]
  58. Tirosh A, Stemmer SM, Solomonov E, Elnekave E, Saeger W, Ravkin Y, et al. Pasireotide for malignant insulinoma. Hormones (Athens). 2016 Apr. 15 (2):271-6. [View Abstract]
  59. Oziel-Taieb S, Maniry-Quellier J, Chanez B, Poizat F, Ewald J, Niccoli P. Pasireotide for Refractory Hypoglycemia in Malignant Insulinoma- Case Report and Review of the Literature. Front Endocrinol (Lausanne). 2022. 13:860614. [View Abstract]
  60. Keymeulen B, Bossuyt A, Peeters TL, Somers G. 111In-octreotide scintigraphy: a tool to select patients with endocrine pancreatic tumors for octreotide treatment?. Ann Nucl Med. 1995 Aug. 9(3):149-52. [View Abstract]
  61. Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG, Eastern Cooperative Oncology Group. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005 Aug 1. 23 (22):4897-904. [View Abstract]
  62. Bernard V, Lombard-Bohas C, Taquet MC, Caroli-Bosc FX, Ruszniewski P, Niccoli-Sire P, et al. Efficacy of Everolimus in Patients with Metastatic Insulinoma and Refractory Hypoglycemia. Eur J Endocrinol. 2013 Feb 7. [View Abstract]
  63. FDA approves new treatment for certain digestive tract cancers. U.S. Food & Drug Administration. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm594043.htm. January 26, 2018; Accessed: January 30, 2018.
  64. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017 Jan 12. 376 (2):125-135. [View Abstract]
  65. Bourcier ME, Sherrod A, DiGuardo M, Vinik AI. Successful control of intractable hypoglycemia using rapamycin in an 86-year-old man with a pancreatic insulin-secreting islet cell tumor and metastases. J Clin Endocrinol Metab. 2009 Sep. 94(9):3157-62. [View Abstract]
  66. Brown E, Watkin D, Evans J, Yip V, Cuthbertson DJ. Multidisciplinary management of refractory insulinomas. Clin Endocrinol (Oxf). 2018 May. 88 (5):615-624. [View Abstract]
  67. Moscetti L, Saltarelli R, Giuliani R, et al. Intra-arterial liver chemotherapy and hormone therapy in malignant insulinoma: case report and review of the literature. Tumori. 2000 Nov-Dec. 86(6):475-9. [View Abstract]
  68. Lo CY, Lam KY, Fan ST. Surgical strategy for insulinomas in multiple endocrine neoplasia type I. Am J Surg. 1998 Apr. 175(4):305-7. [View Abstract]
  69. Fernandez Ranvier GG, Shouhed D, Inabnet WB 3rd. Minimally Invasive Techniques for Resection of Pancreatic Neuroendocrine Tumors. Surg Oncol Clin N Am. 2016 Jan. 25 (1):195-215. [View Abstract]
  70. Dexter SP, Martin IG, Leindler L, et al. Laparoscopic enucleation of a solitary pancreatic insulinoma. Surg Endosc. 1999 Apr. 13(4):406-8. [View Abstract]
  71. Grant CS. Surgical aspects of hyperinsulinemic hypoglycemia. Endocrinol Metab Clin North Am. 1999 Sep. 28(3):533-54. [View Abstract]
  72. Biermann MR, Sundar P, Veeramachaneni H, Chawla S, Patel V, Orr J, et al. Radiofrequency ablation for the management of symptomatic pancreatic insulinomas. VideoGIE. 2024 Jan. 9 (1):45-50. [View Abstract]
  73. Dhar J, Samanta J, Nabi Z, Aggarwal M, Facciorusso A, Conti Bellocchi MC, et al. Endoscopic ultrasound-guided radiofrequency ablation of pancreatic insulinoma: a state of the art review. Expert Rev Gastroenterol Hepatol. 2024 Mar 4. 1-17. [View Abstract]
  74. Crinò SF, Napoleon B, Facciorusso A, et al. Endoscopic Ultrasound-guided Radiofrequency Ablation Versus Surgical Resection for Treatment of Pancreatic Insulinoma. Clin Gastroenterol Hepatol. 2023 Oct. 21 (11):2834-2843.e2. [View Abstract]
  75. Mele C, Brunani A, Damascelli B, Tichà V, Castello L, Aimaretti G, et al. Non-surgical ablative therapies for inoperable benign insulinoma. J Endocrinol Invest. 2017 Jul 28. [View Abstract]
  76. Dąbkowski K, Gajewska P, Walter K, Londzin-Olesik M, Białek A, Andrysiak-Mammos E, et al. Successful EUS-guided ethanol ablation of insulinoma, four-year follow-up. Case report and literature review. Endokrynol Pol. 2017. 68 (4):472-479. [View Abstract]
  77. Sada A, Ramachandran D, Oberoi M, Habermann EB, Lyden ML, Dy BM, et al. Ethanol Ablation for Benign Insulinoma: Intraoperative and Endoscopic Approaches. J Surg Res. 2024 Jan. 293:663-669. [View Abstract]
  78. Bosman FT, Carneiro F, Hruban RH, Theise ND. World Health Organization Classification of Tumours of the Digestive System. Lyons, France: IARC; 2010.
  79. Rindi G, Klöppel G, Alhman H, et al., European Neuroendocrine Tumor Society (ENETS). TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006 Oct. 449 (4):395-401. [View Abstract]
  80. Rindi G, Klöppel G, Couvelard A, Komminoth P, Körner M, Lopes JM, et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2007 Oct. 451 (4):757-62. [View Abstract]
  81. [Guideline] Pavel M, Öberg K, Falconi M, Krenning E, Sundin A, Perren A, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020 Apr 6. 23 Suppl 7:vii124-30. [View Abstract]
  82. [Guideline] Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendtro K, Chan JA, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013 May. 42 (4):557-77. [View Abstract]

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).

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).

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).

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).

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).

Stage T N M
IT1N0M0
IIT2N0M0
T3N0M0
IIIT4N0M0
Any TN1M0
IVAny TAny NM1