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Insulinoma

Insulinoma
Author:
Adrian Vella, MD
Section Editor:
David M Nathan, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Jan 2024.
This topic last updated: Dec 01, 2022.

INTRODUCTION — Low blood glucose concentrations were recognized as a feature of several diseases in the 19th century. However, it was not until insulin became available for the treatment of diabetes mellitus in the early 1920s that clinical events similar to those arising from overtreatment with insulin were identified in individuals without diabetes. This observation led to the postulation of a new disease entity called hyperinsulinism [1].

Support for the existence of hyperinsulinism was provided by discovery of a malignant pancreatic islet-cell tumor in a patient who had episodes of severe hypoglycemia in 1927 [2]. Extracts of the tumor caused marked hypoglycemia in rabbits. The first cure of hyperinsulinism by removal of an insulinoma was reported in 1929 [3].

The clinical features, diagnosis, and treatment of insulinomas will be reviewed here. The causes and evaluation of hypoglycemia and the management of metastatic neuroendocrine tumors are discussed separately. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology" and "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis" and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)

CLINICAL FEATURES — 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. However, postprandial hypoglycemia may be a concurrent or even the sole manifestation of hypoglycemia in some patients [4]. The hypoglycemia in persons with insulinoma is primarily due to reduced hepatic glucose output rather than increased glucose utilization [5]. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis" and "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

Evidence suggests that insulinomas arise from cells of the ductular/acinar system of the pancreas rather than from neoplastic proliferation of islet cells [6]. 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 mRNA with increased translation efficiency is present in high amounts in insulinomas when compared with normal islets [7]. (See "Pancreatic beta cell function".)

Incidence — During a six-decade period of observation (1927 to 1986, during which 224 patients had an insulinoma removed during pancreatic exploration performed at the Mayo Clinic), there were eight cases of insulinoma in residents of Olmsted County, Minnesota, indicating an incidence of 0.4 per 100,000 person-years (four cases per million individuals per year) [8]. The distributions by age and sex in a subsequent (1987 to 2007) series from the same institution were similar to those of the earlier cohort [4]. Insulinomas have been observed in all ethnic groups. Insulinomas have been reported in pregnant women, patients with type 2 diabetes [9,10], in one patient with type 1 diabetes [11], and in one patient with chronic kidney disease [12].

Mayo Clinic series — Insulinomas are so rare that few institutions have accrued enough experience to provide meaningful data regarding their demographic characteristics. This discussion will highlight the demographic and incidence data from the relatively large number of patients with insulinomas at the Mayo Clinic and the comprehensive database for residents of Olmsted County (where the Mayo Clinic is located) [4,8,13]. Patients with insulinoma and a prior history of gastric bypass surgery were excluded. The demographic features of patients with insulinoma reported from other centers have usually been similar [14,15].

Distribution of cases by age and sex — For the series observed from 1987 to 2007, there were 237 patients with a median age of 50 years (range 17 to 86 years) at the time of surgery, and 57 percent were women [4]. These findings were similar to those from the prior series that reported data for the period 1927 to 1986 [8] and also comparable with findings in a cohort of 40 Chinese patients with insulinoma studied over a 15-year period [16].

Symptoms and misdiagnosis — The neuroglycopenic symptoms of insulinoma include confusion, visual change, and unusual behavior [13]. Sympathoadrenal symptoms may include palpitations, diaphoresis, and tremulousness [17]. Amnesia for hypoglycemic episodes is common. Weight gain was described in 18 percent of patients [18]. The median duration of symptoms before diagnosis was less than 1.5 years [8], although a few patients had probably been symptomatic for decades.

Overall, symptoms of hypoglycemia occurred exclusively in the fasting state in 73 percent of patients, whereas 21 percent reported both fasting and postprandial symptoms [4]. Six percent of patients reported only postprandial symptoms [4]. During the study period, there was an increase in the frequency of exclusively reported postprandial symptoms (two percent from 1987 to 1992 compared with 10 percent from 2003 to 2007).

As many as 20 percent of patients with insulinoma had been misdiagnosed with a neurologic or psychiatric disorder before the insulinoma was recognized [13,18]. Seizure disorder is another common misdiagnosis [8,17].

MEN1 — Among the 237 patients in one Mayo Clinic cohort, 14 (6 percent) had multiple endocrine neoplasia type 1 (MEN1), of whom 71 percent were men [4]. Thirteen of these patients (93 percent) had benign insulinomas. Twelve patients with MEN1 (86 percent) had multiple islet tumors, as compared with only 3 percent in the rest of the cohort. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

Tumor characteristics — Insulinomas can be single or multiple and benign or malignant. Among the 224 patients in one cohort [8]:

194 (87 percent) had single benign tumors (one being ectopic)

16 (7 percent) had multiple benign tumors

13 (6 percent) had malignant insulinomas, defined as the presence of metastases

1 had islet hyperplasia [11]

The median age of patients with malignant insulinoma was 48 years (range 18 to 61 years), and 77 percent were men.

Patients who experienced failed initial surgery or recurrent disease over the period 1927 to 1986 had an increased prevalence of MEN1 with multiple tumors (25 percent) and malignant insulinomas (13 percent) [8].

Among 103 patients (90 with benign and 13 with malignant insulinoma) studied over a 30-year period, clinical characteristics and diagnostic criteria did not differ between patients with benign and malignant disease [19].

DIAGNOSIS AND STAGING — The diagnosis of insulinoma is established by demonstrating inappropriately high serum insulin concentrations during a spontaneous or provoked episode of hypoglycemia (eg, 72-hour fast for patients with fasting hypoglycemia or a mixed-meal test for patients with solely postprandial symptoms). Virtually all insulinomas are islet-cell tumors; there is one report of an insulin-secreting small cell carcinoma of the cervix [20]. Insulinoma must be differentiated from other tumors that produce hypoglycemia through non-insulin mediated mechanisms (eg, insulin-like growth factor 2 production). The diagnostic approach is reviewed in detail separately. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology".)

Staging system — In the TNM staging classification (8th edition, 2017), the staging systems for endocrine pancreatic tumors (table 1) are distinct from those used for exocrine pancreatic tumors [21]. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Staging system'.)

Malignant potential — Malignant insulinomas are rare, and therefore, few data exist regarding their clinical presentation and long-term prognosis. They are generally indolent tumors, and some patients have prolonged survival, even in the presence of liver or lymph node metastases. (See 'Patient survival' below and "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring".)

The biologic behavior of pancreatic endocrine tumors does not always correspond to their histologic characteristics; even malignant tumors show little or no cellular pleomorphism, hyperchromasia, or increased mitotic activity. Thus, staging and grading systems have been developed to better predict long-term outcomes. As an example, the World Health Organization classifies malignant gastroenteropancreatic neuroendocrine tumors using a scheme that is based upon 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 [22]. Another classification scheme estimates malignant potential using similar staging criteria but a simplified grading system (mitotic rate and presence of necrosis) [23].

Differential diagnosis — Other disorders have biochemical findings that simulate those of an insulinoma because they similarly lead to hyperinsulinemia:

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. (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. (See "Noninsulinoma pancreatogenous hypoglycemia syndrome".)

Pancreatic islet abnormalities have been described in patients with post-gastric bypass hypoglycemia [24,25], although this finding has been questioned [26]. In very rare instances, an insulinoma may manifest in the post-bariatric surgery setting. (See "Noninsulinoma pancreatogenous hypoglycemia syndrome", section on 'Hypoglycemia 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. (See "Factitious hypoglycemia", section on 'Ingestion of an oral insulin secretagogue' and "Hypoglycemia in adults without diabetes mellitus: Determining the etiology".)

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) [27]. (See "Factitious hypoglycemia", section on 'Insulin measurements' and "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Interpretation of supervised fast results'.)

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 [28]. 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".)

TUMOR LOCALIZATION

Noninvasive tests — After biochemical diagnosis, imaging techniques are needed to localize the tumor. Accurate preoperative localization of an insulinoma is important for surgical planning and patient counseling, particularly as some tumors are not palpable during surgery [29]. Noninvasive imaging procedures include spiral computed tomography (CT), magnetic resonance imaging (MRI), transabdominal ultrasonography, 111-In-pentetreotide imaging, and fluorine-18-L-dihydroxyphenylalanine positron emission tomography (18F-DOPA PET) [30,31]. The choice of procedure depends upon test availability and local radiologic expertise. Transabdominal ultrasonography and 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 [4].

Gallium Ga-68 DOTATATE PET/CT (a somatostatin-receptor-based imaging modality) is 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 nine of 10 patients and was the only modality that successfully localized the tumor in one patient [32]. However, insulinomas express relatively scant levels of subtype 2 somatostatin receptors and may be less likely to be detected with somatostatin-receptor-based imaging. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Somatostatin-receptor-based imaging'.)

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 [33]. This modality requires further investigation.

Invasive tests — In patients with endogenous hyperinsulinemic hypoglycemia and negative noninvasive radiologic localization studies, endoscopic ultrasonography or a selective arterial calcium stimulation test (SACST) with hepatic venous sampling can be performed to localize the tumor [34,35]. Overall, with appropriate preoperative localization studies plus intraoperative ultrasonography and palpation, the tumor(s) can be identified in 98 percent of patients with insulinoma.

Endoscopic ultrasound — 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) [34,36]. In the larger series (237 patients) from the Mayo Clinic, the sensitivity of endoscopic ultrasound for localization of insulinoma was 75 percent [4].

Selective arterial calcium stimulation — The advantage of SACST is that it is also a dynamic test. 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 [35,37]. This test is based upon the observation that calcium stimulates the release of insulin from hyperfunctional 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 SACST for localization of insulinoma was 93 percent for those patients selected to undergo this procedure [4]. When invasive testing (endoscopic ultrasound and/or SACST) was performed in patients with negative noninvasive (ultrasound, CT abdomen) testing, tumor localization was achieved in all cases from 1998 onward. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology".)

SACST has been evaluated for its ability to differentiate insulinoma from nesidioblastosis. In a retrospective review of 116 cases of endogenous hyperinsulinemic hypoglycemia and negative or inconclusive noninvasive imaging from the Mayo Clinic (1996 to 2014), 42 patients were subsequently shown at surgery to have insulinoma and 74 nesidioblastosis [38]. 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. Whereas a robust response to injected calcium (especially in a single artery) is suggestive of insulinoma and a modest response in more than one artery is compatible with nesidioblastosis, the overlap in response characteristics is such that there is not a criterion of response that provides complete diagnostic accuracy.

TREATMENT

Resection of primary tumor — Surgical removal of the insulinoma is the treatment of choice. (See "Surgical resection of sporadic pancreatic neuroendocrine tumors" and "Surgical resection of sporadic pancreatic neuroendocrine tumors", section on 'Insulinoma'.)

The following procedures were performed in the Mayo Clinic cohort [8]:

Enucleation of the insulinoma – 130 patients

Partial distal pancreatectomy – 73 patients

Enucleation of the insulinoma and partial pancreatectomy – 9 patients

A Whipple procedure (removal of the head of the pancreas, gastrectomy, duodenectomy, and splenectomy) – 1 patient

Total pancreatectomy – 1 patient

The surgical procedure was chosen by the surgeon, and none of the operations in the series (1927 to 1986) were done laparoscopically; laparoscopic procedures since have been performed in selected patients. The rate of surgical complications was approximately 10 percent. (See 'Laparoscopic surgery' below.)

In addition, eight patients with malignant insulinomas underwent biopsy of metastatic lesions, and the tumor was found at autopsy after perioperative death in one patient. Histologic examination of this tumor revealed a malignant islet cell tumor that stained intensively for insulin (picture 1A-B).

Outcome — In the 1927 to 1986 series, the following results were noted after surgery [8]:

196 patients (87.5 percent) were cured, as defined by being totally free of symptoms for at least six months after removal of the insulinoma

19 patients (8.5 percent; 10 with benign insulinomas, eight with malignant insulinomas, and one with islet-cell hyperplasia) had persistent hypoglycemia

5 patients (2.2 percent) developed diabetes mellitus

4 patients (1.8 percent) died perioperatively; all four underwent surgery before 1941

Among the 10 patients who had benign insulinomas and persistent hypoglycemia after initial surgical treatment, six had multiple tumors (four due to multiple endocrine neoplasia type 1 [MEN1]). Five of these six patients underwent reoperation. Three of the five were found to have additional multiple tumors; one was cured, and two developed diabetes mellitus after the second operation. Two patients with single tumors at initial operation had persistent hypoglycemia after the second operation because additional insulinomas were not identified.

For patients with insulinoma related to MEN1, some experienced surgeons recommend local excision of any tumors found in the head of the pancreas plus a distal subtotal pancreatectomy [39]. This approach differs from that in patients with sporadic insulinomas, who typically have a solitary tumor and in whom enucleation is usually successful.

Laparoscopic surgery — In some centers, laparoscopic pancreatic surgery is sometimes performed for small, solitary insulinomas that have been localized preoperatively [40-42]. Intraoperative laparoscopic ultrasound may help minimize the need for conversion to open pancreatic surgery. (See "Surgical resection of sporadic pancreatic neuroendocrine tumors", section on 'Minimally invasive resection'.)

Chemical ablation — Ultrasound-guided fine-needle injection of ethanol into an insulinoma in patients with prohibitively high surgical risk has been conducted with successful resolution of hypoglycemia [43]. Seven patients with insulinoma had resolution of hypoglycemia after injection with the sclerosing agent lauromacrogol [44].

Evaluation for missed insulinoma — Reoperation for missed insulinoma presents unique challenges. First, reconfirmation of the diagnosis is needed. Second, one or more localizing procedures should be performed prior to reoperation. (See 'Tumor localization' above.)

Reoperation for insulinoma should only be performed by a surgeon experienced with this situation and accompanied by highly experienced endocrinologic and radiologic support. Blind pancreatic resection should not be performed if localizing studies fail to detect the tumor [45].

Risk of recurrence — As noted above, 196 patients in the 1927 to 1986 Mayo Clinic series were in postsurgical remission (defined as a six-month period without symptoms after initial insulinoma resection). Among these patients, 11 (6 percent) had recurrent hypoglycemia. Eight of these patients underwent repeat exploration of the pancreas; six had pathologic confirmation of recurrent insulinoma, one had persistent hypoglycemia despite total pancreatectomy, and one died intraoperatively. Pancreatic re-exploration was not performed in the other three patients due to patient age and concern about postoperative diabetes. Recurrence of hypoglycemia within four years of successful insulinoma resection suggests regrowth of residual insulinoma tissue that remained as a result of fracturing of the original tumor during surgery. In this case, the tumor is at the same site as the original tumor [46].

The recurrences occurred from 4 to 18.5 years after the initial operation. The cumulative incidence of recurrence was 6 percent at 10 years and 8 percent at 20 years. Recurrences were more common in patients with MEN1; the cumulative 10- and 20-year recurrence rates were 21 percent at both timepoints compared with 5 and 7 percent in those without MEN1 (p<0.001) (figure 1) [8]. Among four patients with malignant insulinoma who were symptom free for six or more months after the initial operation, two patients had recurrences at four and nine years.

Patient survival — The overall survival rate of patients with insulinoma did not differ from that expected in the general population. Survival, however, was significantly worse in the patients with malignant insulinomas (although better than in patients with acinar pancreatic carcinoma), in older patients, and in those diagnosed early in the period of observation (1927 through 1986) (figure 2) [8].

Some patients with malignant insulinoma appear to have a prolonged disease course. In a series of 10 patients treated at the National Institutes of Health over a 20-year period for metastatic insulinoma, nine remained alive long term (up to 25 years), three with liver metastases [47]. 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. Various treatment modalities were used to control hypoglycemia. In this series, short-term benefits were most often achieved with embolization and diazoxide and less often with radiofrequency ablation, radical debulking surgery, verapamil, octreotide, and chemotherapy.

Medical therapy to control symptomatic hypoglycemia — Medical therapy should be considered 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. The therapeutic choices to prevent symptomatic hypoglycemia include:

Diazoxide (given in divided doses of up to 1200 mg/day) diminishes insulin secretion and is sometimes used for controlling hypoglycemia. It is the preferred agent for patients who require medical therapy [47-49]. However, it can cause hirsutism or marked edema that may require high doses of loop diuretics.

Octreotide, an analog of somatostatin (growth hormone-inhibitory hormone), 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, VIPomas, and carcinoid tumors, efficacy is less predictable for insulinoma-related symptoms [47,50-53]. Nevertheless, it is a reasonable choice for patients with persistent hypoglycemia that is refractory to diazoxide.

Lanreotide, another somatostatin analog that is available internationally and in the United States 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). (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Benefits'.)

Verapamil [47] and phenytoin [54] have also been used with some success. However, neither of these drugs is as effective as tumor resection.

Although experience is limited, at least some data suggest that refractory cases may respond to treatment with everolimus, an inhibitor of the mammalian (mechanistic) target of rapamycin (mTOR). (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'mTOR inhibitors'.)

Radiation therapy — Experience with external beam radiotherapy (EBRT) in the management of islet cell tumors is limited. Although pancreatic neuroendocrine carcinomas were previously considered to be radioresistant, data from published case reports and small case series suggest that radiotherapy can produce high rates of symptom palliation and freedom from local progression in patients who are not candidates for surgical resection [55-58]. There are no data specifically on the rate of symptom control in patients with symptomatic insulinomas.

Liver-directed therapy for metastatic disease — Liver and regional lymph nodes are the most common sites of metastatic disease.

Resection — Hepatic resection is indicated for the treatment of metastatic liver disease in the absence of diffuse bilobar involvement, compromised liver function, or extensive extrahepatic metastases (eg, pulmonary, peritoneal). Although most cases will not be cured by surgery, prolonged survival is often possible, given the slow-growing nature of these tumors. (See "Overview of hepatic resection".)

In general, resection should be considered only for patients with a limited number of hepatic metastases and is most successful when undertaken with curative intent. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)

Hepatic artery embolization — Liver metastases derive most of their blood supply from the hepatic artery, whereas healthy hepatocytes derive most of their blood supply from the portal vein. This provides the rationale for therapeutic embolization of the hepatic artery, with the goal of inducing necrosis of the metastases with minimal damage to normal liver parenchyma.

Hepatic arterial embolization with or without selective hepatic artery infusion of chemotherapy is frequently applied as a palliative technique in patients with symptomatic hepatic metastases who are not candidates for surgical resection. Response rates, as defined by a decrease in hormonal secretion or by radiographic regression, are generally over 50 percent. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)

Radiofrequency ablation and cryoablation — Other approaches to the treatment of hepatic-predominant disease include radiofrequency ablation (RFA) and cryoablation, either alone or in conjunction with surgical debulking. These procedures, which can be performed using percutaneous or laparoscopic approaches, appear to confer less morbidity than either hepatic resection or hepatic artery embolization. However, 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'.)

Radioembolization — An alternative means of delivering focal radiotherapy uses radioactive isotopes (eg, yttrium-90 [90-Y]) that are tagged to glass or resin microspheres and delivered selectively to the tumor via the hepatic artery. Evidence of benefit is limited. In one case report, radioembolization improved refractory hypoglycemia for three months [59]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)

Liver transplantation — The number of patients with liver-isolated metastatic disease in whom orthotopic liver transplantation (OLT) has been attempted is small, and follow-up data are insufficient to judge whether complete cure has truly been achieved. The limited availability of donor organs in many regions has restricted investigation of this procedure. Until more data become available, most clinicians consider liver transplantation an investigational approach for metastatic islet cell tumors, including insulinoma.

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 streptozocin/doxorubicin or a temozolomide-based 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 "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Cytotoxic chemotherapy'.)

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 "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Molecularly targeted therapy' and "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Peptide receptor radioligand therapy'.)

POST-TREATMENT SURVEILLANCE — There are no evidence-based guidelines for follow-up after resection of a malignant insulinoma. Consensus-derived guidelines from the National Comprehensive Cancer Network following treatment for an islet cell tumor include the following [60]:

3 to 12 months postresection – History and physical examination, tumor markers, and CT/MRI.

Long term – History and physical examination with tumor markers (as clinically indicated) every 6 to 12 months. Imaging studies are recommended as clinically indicated.

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: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)

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 not limited to any ethnic group (incidence of 1 case per 250,000 person-years); whereas most insulinomas are sporadic, some are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. (See 'Clinical features' above.)

Symptoms – The characteristic clinical manifestation of an insulinoma is fasting and less commonly postprandial hypoglycemia, with neuroglycopenic symptoms that may or may not be preceded by sympathoadrenal (autonomic) symptoms. (See 'Symptoms and misdiagnosis' above.)

Tumor characteristics – Most insulinomas are solitary and benign. Multiple insulinomas are less common and disproportionately associated with MEN1. Malignant insulinomas are also less common. (See 'Tumor characteristics' above.)

Diagnosis – The diagnosis of insulinoma is established 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). (See 'Diagnosis and staging' above and "Hypoglycemia in adults without diabetes mellitus: Determining the etiology".)

Tumor localization – After biochemical diagnosis, imaging techniques are used to localize the tumor. Accurate preoperative localization of an insulinoma is important. Transabdominal ultrasonography and CT are our preferred initial tests. Endoscopic ultrasonography or arterial stimulation with hepatic venous sampling are reserved for insulinomas that cannot be localized through noninvasive techniques. (See 'Diagnosis and staging' above and 'Tumor localization' above.)

Treatment – For initial therapy of patients with benign, solitary insulinomas, we recommend surgical excision of the tumor (Grade 1A). The approach and extent of surgery should be determined based upon tumor location. (See 'Resection of primary tumor' above.)

Multiple insulinomas – For patients with multiple insulinomas (typically in the setting of MEN1), we suggest local excision of any tumors found in the head of the pancreas plus a distal subtotal pancreatectomy (Grade 2B). (See 'Resection of primary tumor' 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 1A). (See 'Resection of primary tumor' above.)

Medical therapy – For patients whose insulinoma cannot be located during pancreatic exploration or those who are not candidates for or refuse surgery, we suggest diazoxide therapy for the medical management of hypoglycemia (Grade 2C). (See 'Medical therapy to control symptomatic hypoglycemia' above.)

The efficacy of somatostatin analogs for patients with diazoxide-refractory symptomatic hypoglycemia is unpredictable, but some patients may benefit. Octreotide, as well as other systemic therapy approaches (interferon, chemotherapy, targeted radiotherapy), are discussed in detail elsewhere. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion".)

Metastatic disease – For patients with potentially resectable liver-isolated metastatic insulinoma, we recommend surgical resection of the hepatic metastases along with the primary tumor (Grade 1B). Although the majority of cases will not be cured by surgery, extended survival is sometimes possible given the slow-growing nature of the tumor. (See 'Resection' above.)

Other treatment options for patients with unresectable, hepatic-predominant, symptomatic metastatic disease include embolization, chemoembolization, radiofrequency ablation (RFA), and cryoablation. (See 'Liver-directed therapy for metastatic disease' above.)

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

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Topic 2187 Version 30.0

References

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