Insulinoma

Authors:
F John Service, MD, PhD
Adrian Vella, MD
Section Editor:
David M Nathan, MD
Deputy Editor:
Jean E Mulder, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Feb 2018. | This topic last updated: Dec 22,
2016.

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 nondiabetic persons.
This observation led to the postulation of a new disease entity called hyperinsulinism
[1].

Support for the existence of hyperinsulinism was provided by finding 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: Diagnostic approach" and "Hypoglycemia in adults: Clinical
manifestations, definition, and causes" and "Metastatic gastroenteropancreatic
neuroendocrine tumors: Local options to control tumor growth and symptoms of
hormone hypersecretion".)

CLINICAL FEATURES — The common clinical manifestation of an insulinoma is fasting

hypoglycemia, with discrete episodes of neuroglycopenic symptoms that may or may
not be preceded by sympathoadrenal (autonomic) symptoms. However, postprandial
hypoglycemia may be a feature 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: Clinical manifestations, definition, and
causes" and "Physiologic response to hypoglycemia in normal subjects 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 at their first pancreatic exploration, which took
place 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 (or four
cases per million per year) [8]. The distributions by age and gender 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.

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) [4,8,9]. Patients with insulinoma and a prior history of gastric bypass were
excluded. The demographic features reported from other centers have usually been
similar [10,11].

Distribution of cases by age and sex — For the series observed from 1987 to 2007,
there were 237 patients, the median age (and range) at the time of surgery was 50 years
(range 17 to 86 years), and 57 percent were women [4]. There were no demographic
differences between this series and that reported for the period 1927 to 1986 [8].

Symptoms — The neuroglycopenic symptoms of insulinoma included confusion, visual

change, and unusual behavior [9]. Sympathoadrenal symptoms may include
palpitations, diaphoresis, and tremulousness [12]. Amnesia for hypoglycemia is
common.

The median duration of symptoms before diagnosis was less than 1.5 years [8].
However, a few patients had probably been symptomatic for decades. As many as 20
percent of patients had been misdiagnosed with a neurologic or psychiatric disorder
before the insulinoma was recognized [9,13]. Seizure disorder is another common
misdiagnosis [8,12]. Weight gain was described in 18 percent of patients [13].
Overall, symptoms of hypoglycemia occurred exclusively in the fasting state in 73
percent, whereas 21 percent reported both fasting and postprandial symptoms, and 6
percent reported only postprandial symptoms [4]. During the period of study, there was
an increase in the frequency of reporting only postprandial symptoms (2 percent from
1987 to 1992 compared with 10 percent from 2003 to 2007).

MEN1 — Among the 237 patients in one cohort, 14 (6 percent) had multiple endocrine
neoplasia type 1 (MEN1), of whom 71 percent were men [4]. Thirteen (93 percent) had
benign insulinomas. Twelve (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 distribution — 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 [14]

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

Patients who required additional surgical treatment because of failed initial surgery or
recurrence of insulinoma over the period 1927 to 1986 had an increased prevalence of
MEN1 with multiple tumors (25 percent) and malignant insulinomas (13 percent) [8].

Insulinomas have been reported in pregnant women, patients with type 2 diabetes
[15,16], in one patient with type 1 diabetes [14], and in one patient with renal failure [17].

DIAGNOSIS AND STAGING — The diagnosis of insulinoma is established by

demonstrating inappropriately high serum insulin concentrations during a spontaneous
or induced episode of hypoglycemia, eg, 72-hour fast for a patient with fasting
hypoglycemia, or in the case of the patient with solely postprandial symptoms, the
mixed-meal test. Virtually all insulinomas are islet-cell tumors; there is one report of an
insulin-secreting small cell carcinoma of the cervix [18]. Other tumors can produce
hypoglycemia by different mechanisms, such as the production of insulin-like growth
factor-2. The diagnostic approach is reviewed in detail separately. (See "Hypoglycemia
in adults without diabetes mellitus: Diagnostic approach".)

Staging system — Pancreatic endocrine tumors such as insulinomas are included in

the combined American Joint Committee on Cancer (AJCC)/Union for International
Cancer Control (UICC) TNM (tumor-node-metastasis) staging system for pancreatic
tumors; the current version (7 edition, 2010) includes both pancreatic endocrine and
th
exocrine tumors (table 1) [19]. Five- and 10-year survival rates for patients undergoing
resection for a pancreatic neuroendocrine tumors (not just insulinomas) stratified by
stage at presentation are presented in the table (table 2) [20].

In the newest release of the TNM staging classification (8 edition, 2017), which is
th

scheduled to take effect on January 1, 2018, the staging systems for endocrine
pancreatic tumors (table 3) is separate from that used for exocrine pancreatic tumors
[21]. Outside of the United States, the UICC has implemented the 8 edition changes as
th

of January 1, 2017. (See "Classification, epidemiology, clinical presentation,

localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Staging
system'.)

Malignant potential — Malignant insulinomas are rare and, therefore, there are few
data 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 study and predict long-term outcomes. As an
example, the World Health Organization estimates the malignant potential of
gastroenteropancreatic neuroendocrine tumors using a classification 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 — There are other disorders in which the biochemical findings
simulate those of an insulinoma because they are also associated with
hyperinsulinemia:

●Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), which is also called

familial hyperinsulinism, congenital hyperinsulinemia, and primary islet cell
hypertrophy (nesidioblastosis), is a genetic disorder that is usually transmitted as
an autosomal recessive trait, but autosomal dominant inheritance has been
described. (See "Pathogenesis, clinical features, and diagnosis of persistent
hyperinsulinemic hypoglycemia of infancy".)
●Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) presents in
adults and is also associated with islet hypertrophy and nesidioblastosis. An
unusual 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 'Nesidioblastosis 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 occurrence, ie, no relation at all to meals or fasting. In
some cases, the clinical presentation can appear similar to that of an insulinoma.
The appropriate application and interpretation of available tests will preclude
surgical exploration in such patients. (See "Factitious hypoglycemia", section on
'Ingestion of an oral insulin secretagogue' and "Hypoglycemia in adults without
diabetes mellitus: Diagnostic approach", section on 'Approach to testing'.)
●Insulin autoimmune hypoglycemia occurs 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, it
has been postulated that insulin secreted in response to a meal binds to the
antibody and then disassociates in an unregulated fashion causing
hyperinsulinemia and hypoglycemia. In patients with antibodies to the insulin
receptor, hypoglycemia occurs as a result of antibody activation of the receptor
[27]. The presence of insulin or insulin receptor antibodies can distinguish insulin
autoimmune hypoglycemia from insulinoma. The antibodies do not have to be
measured during an episode of hypoglycemia. (See "Hypoglycemia in adults
without diabetes mellitus: Diagnostic approach".)

TUMOR LOCALIZATION

Noninvasive tests — After diagnosis, imaging techniques are then used to localize the
tumor. Accurate preoperative localization of an insulinoma is desirable because some
tumors may not be palpable at the time of surgery, and patients can be advised of the
type of surgery planned [28]. The noninvasive procedures available 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) [29,30]. The
choice of procedure depends upon which tests are available and local radiologic skill.
Transabdominal ultrasonography is our preferred initial test. In a series of 237 patients
with insulinoma who were evaluated at the Mayo Clinic, the rate of detection by
transabdominal ultrasound and triple-phase spiral CT of the pancreas was
approximately 70 percent [4].
Pentetreotide scintigraphy will miss up to 40 percent of insulinomas because these
tumors do not express a sufficient number of subtype 2 somatostatin receptors [29,31].
(See "Classification, epidemiology, clinical presentation, localization, and staging of
pancreatic neuroendocrine neoplasms".)

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 [32]. 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 [33,34]. Overall, with appropriate preoperative
localization studies plus intraoperative ultrasonography and palpation, a tumor (or
tumors) can be identified in 98 percent of patients with insulinomas.

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) [31,33].
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
[34,35]. 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: Diagnostic approach", section on 'Arterial calcium
stimulation'.)

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 [36]. 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
will provide 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 via the laparoscope. Since then, a few cases have
been managed laparoscopically. The rate of surgical complications was approximately
10 percent.

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 (2.2 percent) developed diabetes mellitus
●4 (1.8 percent) died perioperatively; all four were operated on 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 [37]. 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 [38,39]. 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'.)

Ethanol 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 [40].

Evaluation for missed insulinoma — Reoperation for missed insulinoma presents

unique problems. First, the diagnosis must be confirmed. Second, one or more
localizing procedures should be done. (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 a tumor is not identified
[41].

Risk of recurrence — As noted above, 196 patients in the 1927 to 1986 series were in
remission soon after surgery (defined as a six-month period free of symptoms after
initial removal of an insulinoma). 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 reexploration
was not performed in the other three patients, because of age and concerns about
diabetes. Recurrence of hypoglycemia within four years of the successful removal of an
insulinoma suggests regrowth of residual insulinoma tissue left behind as a result of
fracturing of the original tumor. In this case, the tumor is at the same site as the original
tumor [42].

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 the patients with MEN1; the cumulative 10- and
20-year recurrence rates were 21 percent at both times 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 (but 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 natural history. In
a series of 10 patients treated at the National Institutes of Health (NIH) over a 20-year
period for metastatic insulinoma, nine remained alive long term (up to 25 years), three
with liver metastases [43]. Four had developed metastatic disease from 4 to 12 years
after initial diagnosis, while four had resected lymph node metastases as the only site
of 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 the patient whose insulinoma was missed during pancreatic
exploration, who is not a candidate for or refuses surgery, or who has unresectable
metastatic disease. The therapeutic choices to prevent symptomatic hypoglycemia
include:

●Diazoxide (which diminishes insulin secretion and is given in divided doses of up

to 1200 mg/day) is sometimes used for controlling hypoglycemia [43-45]. However,
it can cause marked edema (which may require high doses of loop diuretics) and
hirsutism.
●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. While octreotide is
highly effective in controlling the symptoms associated with glucagonomas,
VIPomas, and carcinoid tumors, efficacy is less predictable for symptomatic
 patients with insulinoma [43,46-49]. 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, and 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 [43] and phenytoin [50] have also been used with some success.
However, none 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 (RT) can produce high rates of
symptom palliation and freedom from local progression in patients who are not
candidates for surgical resection [51-54]. There are no data specifically on the rate of
symptom control in patients with symptomatic insulinomas.

Liver-directed therapy for metastatic disease — The 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 the majority of
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 measured 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 artery embolization'.)

RFA 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 be less morbid 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 RT 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
[55]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to
control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic
artery 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 that liver
transplantation is 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, renal
failure), has 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,
performance status, and the anticipated side-effect profile of both combinations.
(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'.)

POSTTREATMENT 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 [56]:

●Three and six months postresection – History and physical examination, tumor
markers, and computed tomography (CT)/magneticresonance imaging (MRI).
●Long term – History and physical examination with tumor markers every 6 to 12
months for years 1 to 3, and as clinically indicated thereafter. Imaging studies are
recommended only as clinically indicated.

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SUMMARY AND RECOMMENDATIONS

●Insulinomas are rare pancreatic islet cell tumors not limited to any ethnic group
(incidence of 1 case per 250,000 person-years); while most are sporadic, some are
associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. The
characteristic clinical manifestation of an insulinoma is fasting hypoglycemia,
(although some patients also have postprandial hypoglycemia), with
neuroglycopenic symptoms that may or may not be preceded by sympathoadrenal
(autonomic) symptoms. (See 'Clinical features'above.)
Most insulinomas are solitary and benign. Multiple insulinomas are less common
and tend to be associated with MEN1. Malignant insulinomas are also less
common. (See 'Tumor distribution' above.)
●The diagnosis of insulinoma is established by demonstrating inappropriately high
serum insulin concentrations during a spontaneous or induced 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: Diagnostic approach".)
Imaging techniques are then used to localize the tumor. Accurate preoperative
localization of an insulinoma is desirable. Transabdominal ultrasonography and
computed tomography (CT) are our preferred initial test, followed by endoscopic
ultrasonography or arterial stimulation with hepatic venous sampling when an
insulinoma has not been localized by noninvasive techniques. (See 'Diagnosis and
staging' above and 'Tumor localization' above.)
●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.)
●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.)
●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.)
●For patients whose insulinoma cannot be located during pancreatic exploration,
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.)
●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,
given the slow-growing nature of the tumor, extended survival is sometimes
possible. (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.)
●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 [RT]), are discussed in detail elsewhere.
(See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic
therapy options to control tumor growth and symptoms of hormone
hypersecretion".)

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