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تعداد آیتم قابل مشاهده باقیمانده : -22 مورد

Insulinoma

Insulinoma
Author:
Adrian Vella, MD
Section Editor:
David M Nathan, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Apr 2025. | This topic last updated: Mar 10, 2025.

INTRODUCTION — 

In the 19th century, low blood glucose concentrations were recognized as a feature of several diseases. In the 1920s, the advent of insulin therapy for diabetes led to recognition that individuals without diabetes could experience clinical events resembling episodes of insulin overtreatment. Based on this observation, a new disease entity called hyperinsulinism was postulated [1] and soon supported by the discovery of a malignant pancreatic islet cell tumor in a patient with episodes of severe hypoglycemia [2]. Extracts from the islet cell tumor caused marked hypoglycemia in rabbits. Surgical removal of an insulinoma was initially reported in 1929 and cured hyperinsulinism [3].

This topic will review the clinical features, diagnosis, and treatment of insulinomas. The causes and evaluation of hypoglycemia and the management of metastatic neuroendocrine tumors are discussed separately. Details regarding surgical resection of insulinoma are also presented elsewhere.

(See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis".)

(See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology".)

(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)

(See "Surgical resection of sporadic pancreatic neuroendocrine neoplasms".)

EPIDEMIOLOGY AND PATHOGENESIS

Incidence — Insulinomas are rare tumors, and the incidence is estimated largely based on single-center case series. For example, data from a six-decade period of observation (1927 to 1986) at the Mayo Clinic demonstrated an incidence of 0.4 per 100,000 person-years (four cases per million individuals per year) [4]. A retrospective analysis in Sweden found an estimated incidence of 0.13 cases per 100,000 person-years [5]. A study in Japan reported an incidence of 0.33 per 100,000 person-years and a ratio of benign to malignant insulinomas of approximately 8:1 [6].

Demographics — Case series have demonstrated a median age at diagnosis of approximately 47 to 56 years [5,7-9], with a broad age range (8 to 86 years across cohorts) [7-9]. The incidence is generally comparable in males and females, although a few series have found a slight female predominance [4,7,10]. Rarely, insulinomas have presented in the setting of pregnancy, type 2 diabetes, type 1 diabetes, or chronic kidney disease [11-14]. In a series of 103 patients (90 with localized and 13 with metastatic insulinoma) studied over a 30-year period, demographic characteristics did not differ between patients with indolent and aggressive disease [15]. (See 'Tumor characteristics' below.)

Approximately 5 to 8 percent of insulinomas are associated with multiple endocrine neoplasia type 1 [4,9,16,17]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Insulinoma'.)

Pathophysiology — Evidence suggests that insulinomas arise from cells of the ductular/acinar system of the pancreas rather than from neoplastic proliferation of islet cells [18]. In normal islet beta cells, falling glucose concentrations inhibit insulin secretion. The mechanism by which insulinomas maintain high levels of insulin secretion in the presence of hypoglycemia is unknown. However, one study reported that a variant of insulin messenger ribonucleic acid (mRNA) with increased translation efficiency is present in high amounts in insulinomas when compared with normal islets [19]. (See "Pancreatic beta cell function" and "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

CLINICAL FEATURES

Clinical presentation — The most common clinical manifestation of an insulinoma is fasting hypoglycemia with recurrent episodes of neuroglycopenic symptoms that may or may not be preceded by sympathoadrenal (autonomic) symptoms (table 1). In people without diabetes, hypoglycemia is defined based on neuroglycopenia, which typically occurs as glucose levels fall below 55 mg/dL (3 mmol/L). (See 'Biochemical diagnosis' below and "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis".)

The hypoglycemia in persons with insulinoma is primarily due to reduced hepatic glucose output rather than increased glucose utilization [20]. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

Neuroglycopenic and sympathoadrenal symptoms — The neuroglycopenic symptoms of insulinoma include confusion, visual change, and unusual behavior [21]. Altered consciousness and amnesia for hypoglycemic episodes are common [16,22,23]. Sympathoadrenal symptoms may include palpitations, diaphoresis, and tremulousness [24]. Hyperphagia also may be present, and unintentional weight gain has been reported in approximately 20 to 50 percent of patients [16,22,23].

Timing of hypoglycemia — Although fasting hypoglycemia is the most common presentation of insulinoma, postprandial hypoglycemia may be a concurrent or even the sole manifestation of hypoglycemia in some patients [7]. In a Mayo Clinic series of 237 patients with insulinoma, 73 percent of patients experienced hypoglycemia exclusively in the fasting state, whereas 21 percent reported both fasting and postprandial symptoms [7]. Exclusively postprandial symptoms were reported by 6 percent of patients [7].

Delayed diagnosis and misdiagnosis — As many as 20 percent of patients with insulinoma are misdiagnosed with a neurologic or psychiatric disorder before the insulinoma is recognized [21,22]. Seizure disorder is a common misdiagnosis [4,24]. The reported duration of symptoms before diagnosis varies widely, from several months to several decades [4,23].

Tumor characteristics — Insulinomas can be single or multiple, localized or metastatic. Whereas most insulinomas are solitary tumors, approximately 10 percent of patients have multiple intrapancreatic tumors [16,21]. The vast majority (≥90 percent) of insulinomas remain localized to the pancreas [4,9,16]. Tumors are typically small, with an average size of approximately 1.5 cm, and may be difficult to localize through preoperative imaging [4]. Pathologic appearance alone cannot determine whether a tumor is likely to be indolent and confined to the pancreas as opposed to aggressive and likely to metastasize. Extension outside the pancreas is therefore used as a marker of an aggressive clinical course and risk of future recurrence. (See 'Tumor localization' below and 'Tumor staging' below.)

For example, among 224 patients in one cohort [4]:

194 (87 percent) had single, localized tumors (one ectopic)

16 (7 percent) had multiple, localized tumors

13 (6 percent) had metastatic disease

1 had islet hyperplasia [13]

In this cohort, underlying multiple endocrine neoplasia type 1 (MEN1) was more common among patients in whom initial surgery was noncurative or who experienced disease recurrence [4]. A higher prevalence of MEN1 also was found among patients with multiple tumors (25 percent) and metastatic disease (13 percent) compared with a prevalence of 7.6 percent in the overall cohort. Similarly, in another Mayo Clinic cohort, 86 percent of patients with MEN1 had multiple islet tumors, as compared with only 3 percent in the rest of the cohort [7]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

DIAGNOSIS AND STAGING

Biochemical diagnosis — The presence of a hypoglycemic disorder is established by Whipple's triad; the patient must have symptoms of neuroglycopenia, a low plasma glucose concentration at the onset of symptoms, and resolution of symptoms after plasma glucose is raised. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis", section on 'Diagnostic evaluation'.)

The diagnosis of insulinoma requires demonstrating inappropriately high serum insulin concentrations during a spontaneous or provoked episode of hypoglycemia (eg, up to a 72-hour fast for patients with fasting hypoglycemia or a mixed-meal test for patients with solely postprandial symptoms) (algorithm 1 and algorithm 2). Insulinoma must be differentiated from other tumors that cause hypoglycemia through non-insulin mediated mechanisms (eg, insulin-like growth factor 2 production), an entity called nonislet cell tumor hypoglycemia. The approach to making a biochemical diagnosis of insulinoma is reviewed in detail separately. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology" and "Nonislet cell tumor hypoglycemia".)

Tumor localization — After biochemical diagnosis, imaging is needed to localize the tumor. Overall, with appropriate preoperative localization studies plus intraoperative ultrasonography and palpation, the tumor(s) can be identified in 98 percent of patients with insulinoma.

Accurate preoperative localization of an insulinoma is important for surgical planning and patient counseling, particularly as some tumors are not palpable during surgery [25]. Virtually all insulinomas are islet cell tumors; there is one report of an insulin-secreting small cell carcinoma of the cervix [26].

Preferred initial tests — Transabdominal ultrasonography and spiral computed tomography (CT) are our preferred initial tests. In a series of 237 patients with insulinoma who were evaluated at the Mayo Clinic, the combined rate of detection by transabdominal ultrasound and triple-phase spiral CT of the pancreas was approximately 70 percent [7]. In a series of 40 patients with insulinoma in China, enhanced CT successfully localized insulinoma in 85 percent of patients [10].

Insulinoma not localized through initial tests — If the insulinoma is not localized through initial imaging studies, additional options include other noninvasive tests or invasive tests (eg, endoscopic ultrasound, selective arterial calcium stimulation). The order in which these tests are performed may be determined by availability, local expertise in their performance and interpretation, and the preferences of the consulting surgeon. However, it is reasonable to prioritize noninvasive testing first before proceeding to more expensive and/or more invasive testing [27].

Endoscopic ultrasound — If initial, noninvasive radiologic studies are negative, endoscopic ultrasonography can be performed to localize the tumor [28,29]. In small case series, the sensitivity of endoscopic ultrasound for the detection of insulinoma confirmed by surgery but not detected by transabdominal ultrasonography or CT ranged from 82 to 85 percent (image 1) [28,30]. In the series of 237 patients from the Mayo Clinic, the sensitivity of endoscopic ultrasound for localization of insulinoma was 75 percent [7]. In the series from China, endoscopic ultrasound localized insulinoma in 83 percent of patients [10].

Other noninvasive tests — Other noninvasive imaging procedures include magnetic resonance imaging (MRI), 111-In-pentetreotide imaging, and fluorine-18-L-dihydroxyphenylalanine positron emission tomography (18F-DOPA PET) [31,32]. Gallium Ga-68 DOTATATE PET/CT (a somatostatin receptor-based imaging modality) is also an option when conventional imaging studies do not identify an insulinoma. In a retrospective analysis of 31 patients with insulinoma, Ga-68 DOTATATE PET/CT correctly localized the insulinoma in 9 of 10 patients and was the only modality that successfully localized the tumor in one patient [33]. However, insulinomas express relatively scant levels of subtype 2 somatostatin receptors and may be difficult to detect with somatostatin receptor-based imaging. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Somatostatin receptor-based imaging studies'.)

Many insulinomas have high concentrations of glucagon-like peptide 1 (GLP-1) receptors. GLP-1 radioligands that bind to the GLP-1 receptor have been developed. In a small series, GLP-1 receptor scintigraphy successfully localized insulinoma in six patients [34]. This modality requires further investigation.

Findings from a meta-analysis suggested that PET/CT showed superior performance to single-photon emission CT (SPECT)/CT, CT, or MRI and that GLP-1 receptor-based PET/CT was superior to all the other noninvasive diagnostic modalities [35]. However, the reported sensitivity for CT was lower than reported in other case series [7].

Selective arterial calcium stimulation — The advantage of the selective arterial calcium stimulation test is that it is also a dynamic test. Although it is usually performed after other imaging modalities including endoscopic ultrasound are negative, this is not always the case. For example, when planning surgery for a patient with MEN1 and multiple pancreatic lesions, it may help regionalize active tumor(s).

Test procedure and performance – Arterial calcium stimulation with hepatic venous sampling involves selective injection of calcium gluconate into the gastroduodenal, splenic, and superior mesenteric arteries with subsequent sampling of the hepatic venous effluent for insulin [29,36]. This test is based on the observation that calcium stimulates the release of insulin from hyperfunctioning beta cells (insulinomas or nesidioblastosis) but not normal beta cells. Calcium stimulates insulin release in the same arterial territory as the abnormal beta cells, which facilitates operative localization.

In the Mayo Clinic series of 237 patients with insulinoma, the sensitivity of the selective arterial calcium stimulation test for localizing insulinoma was 93 percent in the patient subset that underwent this procedure [7]. When invasive testing (endoscopic ultrasound and/or selective arterial calcium stimulation test) was performed in patients with negative noninvasive (ultrasound, CT abdomen) testing, tumor localization was achieved in all cases from 1998 onward.

Differentiating between insulinoma and nesidioblastosis – Selective arterial calcium stimulation has been evaluated for its ability to differentiate insulinoma from nesidioblastosis. Nesidioblastosis describes neoformation of islets of Langerhans from pancreatic duct epithelium; if these islets are hyperfunctioning, nesidioblastosis can lead to noninsulinoma pancreatogenous hypoglycemia syndrome. In a retrospective review of 116 cases of endogenous hyperinsulinemic hypoglycemia and negative or inconclusive noninvasive imaging, 42 patients were subsequently shown at surgery to have insulinoma and 74 nesidioblastosis [37]. Using maximum increase in hepatic venous insulin concentration over baseline after calcium injection, cutpoints of >91.5 microinternational units/mL and >263.5 microinternational units/mL were 95 and 100 percent specific for insulinoma, respectively. In addition, a 19-fold increase in hepatic venous insulin over baseline was 99 percent specific for insulinoma. A robust response to injected calcium (especially in a single artery) suggests insulinoma, whereas a modest response in more than one artery is compatible with nesidioblastosis; however, the overlap in response characteristics is such that no single criterion provides complete diagnostic accuracy. (See 'Differential diagnosis' below and "Noninsulinoma pancreatogenous hypoglycemia syndrome".)

Tumor staging — The biologic behavior of pancreatic endocrine tumors does not always correspond to their histologic characteristics; even metastatic tumors show little or no cellular pleomorphism, hyperchromasia, or increased mitotic activity. Staging and grading systems have been developed to better predict long-term outcomes.

In the ninth version of the American Joint Committee on Cancer (AJCC) TNM staging classification, the staging systems for well-differentiated pancreatic neuroendocrine tumors (table 2) are distinct from those used for exocrine pancreatic tumors [38]. Staging of pancreatic neuroendocrine tumors is reviewed in detail elsewhere. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Staging system'.)

Alternative classification systems also have been developed. As an example, the World Health Organization classifies malignant gastroenteropancreatic neuroendocrine tumors using a scheme that is based on stage-related (ie, tumor size <2 versus >2 cm and the presence of metastases) and grade-related (mitotic rate, perineural and lymphovascular invasion, Ki-67 proliferative index) criteria [39]. Another classification scheme estimates malignant potential using similar staging criteria but a simplified grading system (mitotic rate and presence of necrosis) [40].

Differential diagnosis — Other disorders have biochemical findings that resemble those of an insulinoma because they similarly lead to hyperinsulinemic hypoglycemia:

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), also called familial hyperinsulinism or congenital hyperinsulinemia, is a genetic disorder that is usually transmitted as an autosomal recessive trait, but autosomal dominant inheritance has been described. However, this disorder is uniformly diagnosed in infancy and does not lead to unexplained hypoglycemia in adults. (See "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism".)

Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) presents in adults and is characterized by islet hypertrophy. A distinguishing feature of this disorder is that hypoglycemia occurs postprandially, two to four hours after a meal. Fasting hypoglycemia, characteristic of insulinoma, is rare in this disorder. NIPHS may present similarly to post-gastric bypass hypoglycemia; however, a diagnosis of NIPHS should only be made in individuals who have not undergone a procedure that affects gastric emptying. Selective arterial calcium stimulation can help distinguish between NIPHS and insulinoma. (See 'Selective arterial calcium stimulation' above and "Noninsulinoma pancreatogenous hypoglycemia syndrome".)

Pancreatic islet abnormalities have been described in patients with post-gastric bypass hypoglycemia [41,42], although the etiologic role of islet hyperplasia in this form of hypoglycemia has been questioned [43]. In very rare instances, an insulinoma may manifest in the post-bariatric surgery setting; nonetheless, a history of gastric bypass surgery makes insulinoma unlikely. (See "Noninsulinoma pancreatogenous hypoglycemia syndrome", section on 'Glucose abnormalities after Roux-en-Y gastric bypass surgery'.)

Sulfonylurea-induced hypoglycemia should be considered in every patient undergoing evaluation for a hypoglycemic disorder, especially when the hypoglycemia has a chaotic pattern of occurrence (ie, unrelated to either meal consumption or fasting). In some cases, the clinical presentation can resemble that of an insulinoma. Appropriate biochemical evaluation is essential to prevent unnecessary surgical exploration in such patients (algorithm 2). (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'C-peptide level ≥0.2 nmol/L' and "Factitious hypoglycemia", section on 'Causal agents'.)

Factitious hypoglycemia due to exogenous insulin administration generates different biochemical findings from those of insulinoma. Insulin, C-peptide, and proinsulin are elevated with insulinoma, whereas excessive exogenous insulin is typically characterized by suppressed C-peptide and proinsulin concentrations with variably elevated insulin concentrations (depending on whether the specific analog is detected by the clinical insulin assay) [44]. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Interpretation of supervised fast results' and "Factitious hypoglycemia", section on 'Differentiating factitious hypoglycemia from other etiologies'.)

Autoimmune hypoglycemia disorders occur in patients who have antibodies directed to endogenous insulin or to the insulin receptor. Symptoms can occur postprandially, fasting, or in both states. In patients with insulin autoantibodies, hypoglycemia has been ascribed to the initial, transient binding of insulin to autoantibodies after a meal, followed by unregulated disassociation that causes hyperinsulinemia uncoupled to food consumption. In patients with antibodies to the insulin receptor, hypoglycemia occurs as a result of antibody-mediated activation of the receptor [45]. Measurement of insulin or insulin receptor antibodies distinguishes autoimmune hypoglycemia from insulinoma. Antibody measurement does not have to be performed during an episode of hypoglycemia. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology".)

TREATMENT

Localized disease — For patients with localized disease, surgical removal of the insulinoma is the treatment of choice. (See "Surgical resection of sporadic pancreatic neuroendocrine neoplasms", section on 'Insulinoma'.)

Solitary, localized insulinoma — Surgical approaches to insulinoma removal include tumor enucleation and parenchyma-sparing pancreatic resection. Minimally invasive procedures are often possible. The approach to surgical excision of a solitary, localized insulinoma (including intraoperative localization and minimally invasive strategies [46-48]) is described in detail separately. (See "Surgical resection of sporadic pancreatic neuroendocrine neoplasms", section on 'Insulinoma'.)

In selected patients, insulinoma removal by radiofrequency ablation may be an option [49]. (See "Surgical resection of sporadic pancreatic neuroendocrine neoplasms", section on 'Resection of insulinoma'.)

In patients with prohibitively high surgical risk, ultrasound-guided fine-needle injection of ethanol into an insulinoma has been conducted with successful resolution of hypoglycemia [50]. Seven patients with insulinoma had resolution of hypoglycemia after injection with the sclerosing agent lauromacrogol [51].

Multiple, intrapancreatic tumors — For patients with insulinoma related to multiple endocrine neoplasia type 1 (MEN1), or the rare patient with multiple (functioning) islet tumors in the absence of MEN1, some experienced surgeons recommend local excision of any tumors found in the head of the pancreas plus a distal subtotal pancreatectomy [52]. This approach differs from that in patients with sporadic insulinomas, who typically have a solitary tumor and in whom enucleation is often the optimal approach. However, tumor location (eg, deep in the pancreatic head, adjacent to a large vessel or the pancreatic duct) may necessitate a Whipple procedure, extended distal pancreatectomy, or occasionally intraoperative ablation with ethanol [27].

Persistent postoperative disease — In patients with a biochemical diagnosis of insulinoma, persistent postoperative disease may be due to failure to properly localize the insulinoma, multiple intrapancreatic foci of insulinoma, or undetected metastatic disease. Histologic examination of a resected insulinoma shows intensive staining for insulin (picture 1A-B). Thus, a "missed" insulinoma may be suspected based on a negative pathology report, whereas multifocal or metastatic disease is likely if hypoglycemia recurs despite successful excision of a single tumor.

Frequency of persistent disease – In the Mayo Clinic series of 224 patients with confirmed insulinoma, 19 patients (8.5 percent) had persistent postoperative hypoglycemia [4]. Of these 19 patients, six had multiple tumors, eight had metastatic disease, and one had islet cell hyperplasia. Similar findings were reported in a series of 198 patients with insulinoma who underwent surgery in Italy; in this series, 8.5 percent of patients who underwent insulinoma enucleation required repeat surgery, as did 1 percent of those who underwent initial pancreatic resection [16].

Evaluation for "missed" insulinoma – Reoperation for missed insulinoma presents unique challenges. First, reconfirmation of the biochemical diagnosis is needed. Second, one or more localizing procedures should be performed prior to reoperation. For patients with persistent postoperative hypoglycemia in whom solitary or multiple tumors are identified after additional localization procedures, we recommend repeat operation. (See 'Biochemical diagnosis' above and 'Tumor localization' above.)

Reoperation for insulinoma should only be performed by an experienced surgeon and requires highly experienced endocrinologic and radiologic support. Blind pancreatic resection should not be performed if localizing studies fail to detect the tumor [53].

Metastatic disease — Liver and regional lymph nodes are the most common sites of metastatic disease. In selected patients, hepatic metastases may be resected along with the primary tumor. The management of liver-predominant metastatic disease, including surgical and nonsurgical strategies, is described in detail separately. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic-predominant metastatic disease'.)

Resection – Hepatic resection is indicated for the treatment of metastatic liver disease in the absence of diffuse involvement or extensive extrahepatic metastases. (See "Overview of hepatic resection" and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)

Hepatic artery embolization – Hepatic artery embolization targets the blood supply of hepatic metastases, which mostly derives from the hepatic artery. Therefore, therapeutic embolization induces necrosis of the metastases. This is frequently used to palliate hypoglycemia. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)

Other approaches (limited evidence)

Radiofrequency ablation and cryoablation – Other approaches to the treatment of hepatic-predominant disease include radiofrequency ablation and cryoablation, either alone or in conjunction with surgical debulking. Both techniques are applicable only to smaller lesions, and their long-term efficacy is uncertain. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Ablation'.)

Liver transplantation – Transplantation may be an option in patients with liver-isolated metastatic disease. The number of patients in whom orthotopic liver transplantation has been attempted is small, and follow-up data are insufficient to judge efficacy.

Chemotherapy and novel treatment approaches – Experience with systemic chemotherapy is limited. The traditional regimen of choice has been streptozocin and doxorubicin. Although objective response rates as high as 69 percent were initially reported for metastatic islet cell tumors, the true radiologic response rate is probably lower, between 10 and 40 percent. Uncertainty as to efficacy, as well as the toxicity of this regimen (nausea, prolonged myelosuppression, kidney failure), have prevented its widespread acceptance as a standard first-line therapy.

Antitumor activity has also been shown for regimens containing the orally active alkylating agent temozolomide. In the absence of comparative trials, the choice of first-line regimen must be individualized, taking into account the convenience of oral rather than intravenous treatment, patient performance status, and the anticipated side-effect profile of each regimen. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)

The modest efficacy of conventional cytotoxic chemotherapy has prompted the development of novel therapeutic approaches for patients with advanced islet cell tumors. These include molecularly targeted therapy with small molecule tyrosine kinase inhibitors and inhibitors of the mammalian (mechanistic) target of rapamycin (mTOR), as well as peptide receptor radioligand therapy. These topics are discussed in detail elsewhere. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)

Medical therapy to control symptomatic hypoglycemia — Medical therapy may be needed in patients with insulinoma that is missed during pancreatic exploration, those who are not surgical candidates or opt against surgery, or those who have unresectable metastatic disease. Medical therapy also may be warranted preoperatively to manage recurrent hypoglycemia if surgery is delayed.

Somatostatin analogs, chemotherapy, and other medical strategies to control tumor growth are reviewed separately. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors", section on 'General approach to the patient'.)

Diazoxide (preferred initial agent) — Diazoxide (given in divided doses of up to 1200 mg/day) diminishes insulin secretion and is the preferred agent for patients who require medical therapy [54-56]. In a retrospective study of 20 patients with insulinoma treated with diazoxide, nine patients experienced a therapeutic response [57]. Most patients (n = 17) were treated for preoperative management of hypoglycemia. All patients with a therapeutic response had localized disease, whereas none of the four patients with metastatic disease responded to diazoxide treatment.

Potential adverse effects of diazoxide include hirsutism in female patients, thrombocytopenia, or marked edema that may require high doses of loop diuretics.

Refractory hypoglycemia — For patients with hypoglycemia refractory to diazoxide, somatostatin analogs may be helpful. Other agents also have been used but have fewer supporting data.

Somatostatin analogsOctreotide, an analog of somatostatin, inhibits growth hormone secretion but, in large doses, also inhibits the secretion of thyroid-stimulating hormone (TSH), insulin, and glucagon. Although octreotide is highly effective for controlling the symptoms of glucagonomas, vasoactive intestinal peptide secreting tumors (VIPomas), and carcinoid tumors, efficacy is less predictable for insulinoma-related symptoms [54,58-62]. Nevertheless, it is a reasonable choice for patients with persistent hypoglycemia that is refractory to diazoxide.

Lanreotide, another somatostatin analog used for the treatment of acromegaly, appears to have similar clinical efficacy as octreotide. It is also available in a long-acting depot form (lanreotide SR). The role of somatostatin analogs in the treatment of pancreatic neuroendocrine tumors is reviewed in detail separately. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)

Careful monitoring is necessary when initiating a somatostatin analog [63-65]. Somatostatin analogs may paradoxically worsen hypoglycemia due to simultaneous inhibition of glucagon secretion. 

Other therapiesVerapamil [54] and phenytoin [66] have also been used with some success.

Although experience is limited, some data suggest that refractory cases may respond to treatment with everolimus, an inhibitor of the mTOR [67-71]. For example, in one report of four patients with insulinoma and hypoglycemia refractory to multiple therapies, glycemia improved in all four patients, and two also had evidence of tumor regression [72].

Radiation therapy (limited evidence) — Stereotactic body radiotherapy (SBRT), which uses multiple conformal beams to achieve precise targeting of high-dose radiation to target tissue, has been applied to hepatic neuroendocrine metastases but it is uncertain whether this achieves control of insulin secretion [73].

PROGNOSIS AND SURVEILLANCE

Prognosis

Risk of recurrence — If postsurgical remission is achieved, the chance of recurrent insulinoma is low (<10 percent). In a multicenter study of 198 patients with insulinoma, only 3 percent of patients experienced disease recurrence over a median follow-up of 65 months [16]. Recurrence of hypoglycemia within four years of successful insulinoma resection suggests regrowth of residual insulinoma tissue that remained due to fracturing of the original tumor during surgery. In this case, the tumor is at the same site as the original tumor [74].

Recurrent insulinoma has been described up to approximately 20 years after initial resection. Recurrences are more common in patients with multiple endocrine neoplasia type 1 (MEN1); in the Mayo Clinic series, the cumulative 10- and 20-year recurrence rates were 21 percent at both timepoints in patients with MEN1 compared with 5 and 7 percent, respectively, in those without MEN1 (p<0.001) (figure 1) [4]. Among four patients with malignant insulinoma who were symptom-free for ≥6 months after the initial operation, two patients had recurrences at four and nine years.

Patient survival — The overall survival rate of patients with localized insulinoma does not differ from that expected in the general population. Survival, however, is worse in older patients and in those with metastatic disease (figure 2) [4].

Metastatic insulinomas are rare, and therefore, limited data exist regarding their long-term prognosis. Even when metastatic, insulinomas are generally indolent tumors, and some patients have prolonged survival despite the presence of liver or lymph node metastases. For example, in a series of 10 patients treated for metastatic insulinoma at the National Institutes of Health over a 20-year period, nine remained alive long-term (up to 25 years), three with liver metastases [54]. Four had developed metastatic disease between 4 to 12 years after initial diagnosis, and four had resected lymph node metastases as the only site of extrapancreatic disease. Similarly, in a multicenter case series of 31 patients with metastatic insulinoma, the 5-year survival rate was 62 percent, despite the high prevalence of hepatic (41.9 percent) or widespread (38.7 percent) metastases [75]. (See "Clinical presentation, imaging and biomarker monitoring, and prognosis of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors".)

Post-treatment surveillance — No evidence-based guidelines are available to guide follow-up after resection of an insulinoma. Consensus-derived guidelines are available from the National Comprehensive Cancer Network for surveillance following treatment for an islet cell tumor [76].

Surveillance is usually informed by factors such as completeness of resection, evidence of metastatic disease, or the recurrence/persistence of hypoglycemic symptoms. Imaging studies are recommended as clinically indicated (eg, to monitor suspected metastatic disease) or if symptoms recur. The imaging modality selected is often the same as that which successfully localized the original disease. Follow-up is advised for 10 years post-surgery.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuroendocrine neoplasms".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Low blood sugar in people without diabetes (The Basics)")

SUMMARY AND RECOMMENDATIONS

Clinical features – Insulinomas are rare pancreatic islet cell tumors. Whereas most insulinomas are sporadic, some are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. (See 'Clinical features' above.)

Symptoms – The most common clinical presentation of an insulinoma is fasting hypoglycemia with recurrent episodes of neuroglycopenic symptoms that may or may not be preceded by sympathoadrenal (autonomic) symptoms. (See 'Clinical presentation' above.)

Tumor characteristics – Most insulinomas are solitary and localized to the pancreas. Multiple insulinomas are less common and disproportionately associated with MEN1. Metastatic insulinomas are also less common. (See 'Tumor characteristics' above.)

Diagnosis – The diagnosis of insulinoma is established biochemically by demonstrating inappropriately high serum insulin concentrations during a spontaneous or provoked episode of hypoglycemia (eg, 72-hour fast for fasting hypoglycemia or a mixed-meal test for postprandial hypoglycemia) (algorithm 1 and algorithm 2). (See 'Diagnosis and staging' above and "Hypoglycemia in adults without diabetes mellitus: Determining the etiology".)

Tumor localization – After biochemical diagnosis, imaging is needed to localize the tumor. Accurate preoperative localization of an insulinoma is important. Transabdominal ultrasonography and CT are our preferred initial tests. If these fail to localize the insulinoma, additional options include other noninvasive tests or invasive tests (eg, endoscopic ultrasound, selective arterial calcium stimulation). The order in which these tests are performed may be determined by availability, local expertise in their performance and interpretation, and the preferences of the consulting surgeon. (See 'Diagnosis and staging' above and 'Tumor localization' above.)

Treatment – For initial therapy of patients with localized disease, we recommend surgical removal of the insulinoma (Grade 1B). Outcome data for ethanol or radiofrequency ablation are scarce, and these methods are reserved for patients with high surgical risk or tumor location requiring extensive resection. Unlike surgery, medical therapy does not cure the underlying disease. (See 'Localized disease' above.)

The approach and extent of surgery should be determined based on tumor location. (See "Surgical resection of sporadic pancreatic neuroendocrine neoplasms", section on 'Insulinoma'.)

Multiple insulinomas – For patients with multiple insulinomas (typically in the setting of MEN1), surgical management typically entails local excision of any tumors found in the head of the pancreas plus a distal subtotal pancreatectomy. However, tumor location (eg, deep in the pancreatic head, adjacent to a large vessel or the pancreatic duct) may necessitate a Whipple procedure, extended distal pancreatectomy, or occasionally intraoperative ablation with ethanol. (See 'Localized disease' above.)

Persistent postoperative hypoglycemia – For patients with persistent hypoglycemia after surgery in whom solitary or multiple tumors are identified after additional localization procedures, we recommend repeat operation (Grade 1B). (See 'Localized disease' above.)

Medical therapy – For patients who require medical therapy to manage symptomatic hypoglycemia, we suggest diazoxide therapy rather than somatostatin analogs (Grade 2C). Therapeutic efficacy of diazoxide for managing hypoglycemia is more predictable than that of somatostatin analogs. (See 'Medical therapy to control symptomatic hypoglycemia' above.)

We reserve somatostatin analogs for patients with symptomatic hypoglycemia that is refractory to diazoxide. Octreotide, as well as other systemic therapy approaches (chemotherapy, targeted radiotherapy), are discussed in detail elsewhere. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)

Metastatic disease – Liver and regional lymph nodes are the most common sites of metastatic disease. In selected patients, hepatic metastases may be resected along with the primary tumor. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic-predominant metastatic disease'.)

Prognosis – If postsurgical remission is achieved, the chance of recurrent insulinoma is low (<10 percent). The overall survival rate of patients with localized insulinoma does not differ from that expected in the general population. Survival, however, is worse in older patients and in those with metastatic disease (figure 2). (See 'Prognosis' above.)

Surveillance – Surveillance is usually informed by factors such as completeness of resection, evidence of metastatic disease, or the recurrence/persistence of hypoglycemic symptoms. Imaging studies are recommended as clinically indicated (eg, to monitor suspected metastatic disease) or if symptoms recur. Follow-up is advised for 10 years post-surgery. (See 'Post-treatment surveillance' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges F John Service, MD, PhD, who contributed to an earlier version of this topic.

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