The management of insulinoma O. N. Tucker , P. L. Crotty

Transcription

Review
The management of insulinoma
O. N. Tucker1 , P. L. Crotty2 and K. C. Conlon1
Departments of 1 Surgery and 2 Pathology, The Adelaide and Meath Hospital, Tallaght, Dublin, UK
Correspondence to: Professor K. C. Conlon, Professorial Surgical Unit, Trinity College Dublin, Trinity Building, The Adelaide and Meath Hospital
incorporating The National Children’s Hospital, Tallaght, Dublin 24, UK (e-mail: [email protected])
Background: Insulinomas are rare tumours. Their clinical presentation, localization techniques and
operative management were reviewed.
Methods: An electronic search of the Medline, Embase and Cochrane databases was undertaken for
articles published between January 1966 and June 2005 on the history, presentation, clinical evaluation,
use of imaging techniques for tumour localization and operative management of insulinoma.
Results and conclusion: Most insulinomas are intrapancreatic, benign and solitary. Biochemical
diagnosis is obtained during a supervised 72-h fast. Non-invasive preoperative imaging techniques
to localize lesions continue to evolve. Intraoperative ultrasonography can be combined with other
preoperative imaging modalities to improve tumour detection. Surgical resection is the treatment of
choice. In the absence of preoperative localization and intraoperative detection of an insulinoma, blind
pancreatic resection is not recommended.
Paper accepted 6 November 2005
Published online in Wiley InterScience (www.bjs.co.uk). DOI: 10.1002/bjs.5280
Introduction
Insulinomas are rare tumours. The incidence in individuals
is 1–2 per million per year in the UK. Patients present
with symptoms of hypoglycaemia secondary to insulin
hypersecretion, or with non-specific, episodic symptoms
that could be mistaken for a neuropsychiatric disorder.
Even after biochemical confirmation, localization of an
insulinoma can be challenging. This paper discusses
the clinical presentation and diagnosis of insulinoma,
with particular emphasis on localization techniques, and
discusses the management of these elusive tumours.
Methods
An electronic search of the Medline, Embase and Cochrane
databases was undertaken for articles published between
January 1966 and June 2005, with emphasis on the
history, presentation, clinical evaluation, preoperative
and intraoperative localization techniques and operative
management of insulinoma.
Historical perspective
Paul Langerhans first described pancreatic islets in 18691 .
In 1922, insulin was discovered by Banting and Best2 . Five
Copyright  2006 British Journal of Surgery Society Ltd
Published by John Wiley & Sons Ltd
years later, Wilder et al. reported an islet cell carcinoma
in an orthopaedic surgeon suffering from hypoglycaemic
symptoms3 . William Mayo performed an exploratory
laparotomy on him and found a pancreatic tumour with
multiple liver, lymph node and mesenteric metastases.
An extract prepared from the tumour demonstrated
insulin-like activity on injection into a rabbit3 . Roscoe
Graham performed the first curative operation for benign
insulinoma in 1929 in Toronto. Subsequently, Wermer
reported disorders of one or more endocrine glands in five
members of one family in 1954. This familial syndrome,
once called Wermer syndrome, is now known as multiple
endocrine neoplasia type 1 (MEN-1).
Virtually all insulinomas are intrapancreatic in location.
The median age at presentation is 47 (range 8–82) years,
and there is a female preponderance (female to male ratio
1·4 : 1)4 . Most are solitary lesions, but 10 per cent are
multiple. The lesions are usually small with a diameter
of less than 2 cm in 90 per cent, and less than 1·3 cm
in 50 per cent of patients. Most insulinomas are benign;
only 10 per cent have any evidence of malignancy4 . After
successful surgical excision, the long-term survival is
88 per cent at 10 years with a higher risk of recurrence
in patients with MEN-1.
British Journal of Surgery 2006; 93: 264–275
Management of insulinoma
265
Genetics
Classification of hypoglycaemia
MEN-1 is an autosomal dominant familial cancer
syndrome, characterized by tumours of the parathyroids,
enteropancreatic endocrine tissues and the anterior
pituitary gland5,6 . The syndrome results from inactivation
of the menin gene, a tumour suppressor gene located
on chromosome 11q135,7 . A germline MEN-1 mutation
underlies all or most cases of familial or sporadic MEN-1.
The National Institutes of Health demonstrated germline
MEN-1 mutations in 47 of 50 index cases of MEN-1
and in seven of eight patients with sporadic MEN-18 .
Importantly, a somatic MEN-1 mutation is the most
common gene mutation in many sporadic endocrine
tumours8,9 . Most insulinomas are sporadic in origin, with
only 7·6 per cent associated with MEN-14 . In MEN-1
the mean age at presentation is younger, at 25 years or
less. Interestingly, a somatic MEN-1 mutation has been
described in 17 per cent of sporadic insulinomas8 .
Hypoglycaemia can result from deficient glucose production, excessive glucose use, excessive external glucose
loss, or a combination of these. Hypoglycaemia is further classified as postabsorptive or postprandial (Table 1).
Reproducible postabsorptive hypoglycaemia, commonly
referred to as fasting hypoglycaemia, implies the presence
of disease and requires further evaluation17,18 .
Hypoglycaemia due to excessive endogenous insulin
secretion can be caused by a primary pancreatic β cell
disorder including an insulinoma, β cell hyperplasia or
nesidioblastosis19 , a β cell secretagogue including a sulphonylurea or a β cell-stimulating antibody, or an antibody to
insulin. Non-β cell tumours causing postabsorptive hypoglycaemia include large intrathoracic, intra-abdominal or
retroperitoneal tumours. Tumour types include slowgrowing mesenchymal tumours such as fibrosarcoma,
rhabdomyosarcoma, leiomyosarcoma and mesothelioma,
which make up 50 per cent; 25 per cent are epithelial
tumours, including adrenocortical carcinomas, hepatomas
and carcinoid tumours, and various carcinomas, leukaemias
and lymphomas cause the rest20,21 . Postprandial hypoglycaemia, commonly known as reactive or stimulatory
hypoglycaemia, can be caused by congenital defects of
enzymes of carbohydrate metabolism, gastric surgery or an
idiopathic disorder.
Clinical presentation
Patients with an insulinoma present with symptoms of
hypoglycaemia secondary to excessive and uncontrolled
secretion of insulin. Symptoms are often non-specific,
episodic, vary among individuals and can differ from time
to time in the same individual. Hypoglycaemic symptoms
can be divided into two categories: neuroglycopenic
and neurogenic symptoms10 . Neuroglycopenic symptoms
are due to central nervous system neuronal glucose
deprivation. They include behavioural changes, confusion,
visual changes, fatigue, seizures and loss of consciousness. If
hypoglycaemia is severe and prolonged, death may result11 .
Neurogenic symptoms are due to autonomic nervous
system discharge caused by hypoglycaemia12 . This results
in cholinergic symptoms including hunger, sweating and
parasthesia, and adrenergic symptoms including anxiety,
tremor and palpitations13,14 . Cholinergic symptoms are
mediated by acetylcholine released from sympathetic
postganglionic neurones. Noradrenaline release from
sympathetic postganglionic neurones, the adrenal medulla
or both and adrenaline released from the adrenal medulla
mediate adrenergic symptoms13 .
A shift in glycaemic thresholds for responses to low
plasma glucose occurs in a patient with an insulinoma
resulting in tolerance of abnormally low plasma glucose
levels without symptoms10 . In addition to insulin,
tumours can secrete other hormones, including serotonin,
gastrin, glucagon, somatostatin, pancreatic polypeptide,
corticotrophin and chorionic gonadotropin15,16 .
Table 1
Causes of hypoglycaemia
Postabsorptive hypoglycaemia
Drugs
Insulin
Sulphonylureas
Alcohol
Pentamidine, quinine, propranolol,
haloperidol
Salicylates, sulphonamides
Sepsis
Hepatic failure, cirrhosis
Renal failure
Congestive cardiac failure, shock
Starvation
Hypopituitarism
Addison’s disease
Critical illness
Hormone deficiencies
Non-β cell tumours
Endogenous hyperinsulinaemia
Pancreatic β cell disorder
β cell secretagogue
Autoimmune
Postprandial hypoglycaemia
Congenital deficiencies of enzymes of carbohydrate metabolism
Glycogen storage diseases
Galactosaemia
Hereditary fructose intolerance
Following gastric resection
Idiopathic
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266
Clinical evaluation
Hypoglycaemic symptoms can be non-specific, so it
is important to obtain a plasma glucose level during
symptoms22 . A normal plasma glucose concentration
obtained during symptoms rules out the possibility of an
insulinoma. Whipple’s triad – hypoglycaemic symptoms
in the presence of low plasma glucose with relief
of symptoms on administration of glucose – suggests
endogenous hyperinsulinaemia. In general, venous plasma
glucose levels higher than 3·9 mmol/l after an overnight
fast are normal, levels between 2·8 and 3·9 mmol/l suggest
hypoglycaemia and lower than 2·8 mmol/l indicates
hypoglycaemia. Glycolysis in vitro, otherwise known as
pseudohypoglycaemia, can result in erroneously low
measured glucose levels in the presence of leucocytosis,
thrombocytosis or polycythaemia.
Therapeutically administered antidiabetic drugs, notably
insulin and the sulphonylureas, are the most common cause
of hypoglycaemia23 . Accidental, surreptitious or malicious
administration of these drugs should be considered in
any patient presenting with hypoglycaemia. Commercially
sold insulin preparations contain no C-peptide, so undetectable plasma C-peptide in a patient with hypoglycaemia
and raised insulin levels indicates an exogenous source of
insulin24 . Sulphonylureas result in glucose, insulin and Cpeptide patterns indistinguishable from those produced by
a primary β cell disorder, therefore the measurement of
plasma sulphonylurea level is essential. Insulin receptorstimulating antibodies can cause hypoglycaemia. In these
patients, insulin levels are high, and plasma glucose and
C-peptide levels are low. Antibodies directed to insulin produce hypoglycaemia during the transition period from the
postprandial to postabsorptive state as insulin secreted in
response to an earlier meal slowly dissociates from the antibodies. In these patients, total and free plasma insulin levels
are inappropriately high, insulin secretion is appropriately
suppressed, free plasma C-peptide levels and proinsulin
levels are low, but total C-peptide and proinsulin levels
are high because of cross reactivity with antibody-bound
proinsulin with its C-peptide sequence25,26 .
In the case of an insulinoma, symptoms are typically
evident in the morning after an overnight fast, and are often
precipitated by exercise. Patients learn to avoid symptoms
by eating frequent small meals and sugary snacks, with
resultant weight gain. A supervised 72-h fast forms the
basis for the diagnosis of endogenous hyperinsulinaemia27 .
The critical pathophysiological feature is failure of insulin
secretion to fall to very low rates during episodes of
hypoglycaemia22 . After admission to hospital, intravenous
access is established, and the patient is allowed to drink
only water during the fast, and encouraged to exercise. A
O. N. Tucker, P. L. Crotty and K. C. Conlon
sample of blood is taken every 6 h or when the patient
is symptomatic, for plasma glucose, insulin, C-peptide,
sulphonylurea screen and β-hydroxybutyrate level. The fast
is ended when the plasma glucose falls below 2·2 mmol/l
in association with hypoglycaemic symptoms. The patient
then receives 1 mg of intravenous glucagon, and plasma
glucose is measured after 10, 20 and 30 min. From
published reports, symptoms develop in 35 per cent of
patients within 12 h, 75 per cent within 24 h, 92 per cent
within 48 h and 99 per cent within 72 h27 .
The presence of hypoglycaemic symptoms with fulfilment of the following criteria is diagnostic for insulinoma:
blood glucose level 2·5 mmol/l or lower, insulin level
6 µunits/ml or higher, C-peptide level 0·2 nmol/l or higher,
and a negative sulphonylurea screen (Table 2). In patients
who develop severe symptoms and signs during the 72-h
fast before the diagnostic criteria are fulfilled, additional
evidence in support of the diagnosis can be helpful (Table 2).
A rise in peak plasma glucose concentration by 1·4 mmol/l
or more within 30 min in response to 1 mg of intravenous glucagon at the end of a prolonged fast indicates
hyperinsulinaemia28 . Plasma β-hydroxybutyrate levels are
low in patients with insulinoma because of the antiketogenic effect of insulin. Glucagon given at the end of a
fast results in counteraction of the glycogenic and antiglycolytic effect of insulin. If glycated haemoglobin levels are
lower than 4 per cent (normal 4–7 per cent), this also supports the presence of an insulinoma. Other tests include
C-peptide suppression and tolbutamide tests, which are
not commonly used.
Non-islet cell tumours can cause postabsorptive
hypoglycaemia20 . The pathophysiology includes high rates
of glucose utilization and ectopic insulin secretion. Plasma
insulin, proinsulin and C-peptide levels are appropriately
suppressed during hypoglycaemic episodes in the vast
majority. An incompletely processed form of insulin-like
growth factor II (big IGF-II) is overproduced, which cannot complex normally with circulating binding protein,
resulting in raised free IGF-II and pro-IGF-II levels29,30 .
Growth hormone secretion is suppressed, IGF-I levels are
low and the ratio of IGF-II to IGF-I is raised31 .
Table 2
Diagnostic criteria for insulinoma after a 72-h fast
Factor
Concentration
Plasma glucose
Plasma insulin
Plasma C-peptide
Plasma proinsulin
Plasma sulphonylurea
Plasma β-hydroxybutyrate
Change in glucose with 1 mg glucagon
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≤ 2·5 mmol/l
≥ 6 µunits/ml (43 pmol/l)
≥ 0·2 nmol/l
≥ 0·5 nmol/l
Negative
< 2·7 mmol/l
≥ 25 mg/dl at 30 min
Localization techniques
A number of techniques are available to localize a suspected
insulinoma, including transabdominal ultrasonography,
abdominal computed tomography (CT), magnetic resonance imaging, arteriography, endoscopic ultrasonography
(EUS), transhepatic portal venous sampling, selective arterial calcium stimulation with hepatic venous sampling,
111 In-labelled octreotide scan with single-photon emission
CT, positron emission tomography, intraoperative ultrasonography and intraoperative palpation. In choosing the
localization technique, specific tumour characteristics need
to be considered. It is important to remember that most
tumours are intrapancreatic, 80–90 per cent are solitary,
80 per cent are less than 2 cm in diameter and that they are
distributed equally within the head, body and tail of the
pancreas. Multiple tumours are found in only 8 per cent of
patients associated with MEN-1, and 2 per cent of patients
have diffuse islet cell hyperplasia, microadenomatosis, or
adult nesidioblastosis.
The sensitivity of transabdominal ultrasonography in
the localization of pancreatic insulinomas ranges from
9 to 64 per cent32 – 34 . EUS has been used to improve
accuracy in recent years35 . Sensitivities of up to 94 per cent
(range 57–94 per cent) are reported35,36 . Transabdominal
ultrasonography with frequency probes of 7·5–12 MHz
allows higher image resolution. The EUS appearances of
insulinoma are characteristic and include homogeneous
hypoechoic, rounded lesions with distinct margins35 .
The availability of linear and curvilinear array EUS has
broadened its applicability, with the ability to perform fineneedle aspiration cytology of suspicious lesions, contrastenhanced EUS using Levovist and preoperative marking
of lesions to facilitate surgical excision37 – 39 . Colourcoded Doppler transabdominal ultrasonography allows
imaging of adjacent vessels. However, limitations of EUS
include poor evaluation of lesions in the distal body
or pancreatic tail, inaccurate assessment of malignancy,
poor identification of pedunculated or adjacent lesions
and weak differentiation of larger homogeneous tumours
from surrounding parenchyma40 . Detection rates of
83–100 per cent of head and body lesions are reported
compared with 37–60 per cent for pancreatic tail lesions35 .
Arteriography was considered the ‘gold standard’ for
insulinoma localization. However, improved non-invasive
imaging modalities, combined with reported sensitivities
of 29–64 per cent, have decreased its use34,41,42 . A tumour
blush is seen in only 50–55 per cent of patients32 .
However, Geoghegan et al. correctly identified all solitary
insulinomas in their series using magnification, subtraction
films, superselective arterial catherization and oblique
views43 .
267
Transhepatic portal venous sampling and selective
arterial calcium stimulation with hepatic venous sampling
have been proposed as the most sensitive preoperative
localization techniques by some authors44 – 47 . Transhepatic
portal venous sampling can be used to identify the site
of maximal insulin secretion. The technique involves
transcutaneous, transhepatic needle puncture of the portal
vein, with sequential placement of a sampling catheter
into the splenic, superior mesenteric and portal veins.
Numerous samples are taken to determine the site
of raised insulin production. Selective arterial calcium
stimulation with hepatic venous sampling is based on the
fact that calcium is a potent secretagogue for abnormal
β cells45 . It is a more sensitive and specific provocative
test, and has largely replaced transhepatic portal venous
sampling43,45,47 . An arterial catheter is placed through
the femoral artery into the coeliac axis for subselective
angiography. A separate femoral venous catheter is directed
into the right hepatic vein. An angiogram is performed
followed by selective cannulation of the splenic, superior
mesenteric and gastroduodenal arteries. In general, the
pancreatic body and tail are supplied by the splenic artery,
the head by the gastroduodenal artery and the uncinate
process by branches of the superior mesenteric artery,
although there is considerable overlap. Calcium gluconate
(5 ml bolus of 0·025 mEq/kg) in saline is injected locally
into the gastroduodenal, superior mesenteric and splenic
arteries45 . Samples (5 ml of blood) are taken from the right
hepatic vein before and at 30, 60 and 120 s postinjection
for insulin measurement. A twofold increase in insulin
in the 30- or 60-s sample, or in both, confirms the
diagnosis34 . This technique has a reported sensitivity
of over 90 (range 87·5–100) per cent in the accurate
localization of pancreatic insulinomas44,46 . The sensitivity
is further increased by using selective arterial calcium
stimulation with hepatic venous sampling combined
with intraoperative ultrasonography46 . Although selective
arterial calcium stimulation with hepatic venous sampling
has a high detection rate, it is not used routinely in
most centres as it is invasive, technically demanding and
expensive. It may be appropriate when an insulinoma is
strongly suspected but all non-invasive imaging tests are
negative.
The advent of helical CT scanning has improved
the detection of insulinomas compared with conventional CT36,48,49 . Gouya et al.36 examined the sensitivity
of abdominal CT in the detection of insulinoma in 32
patients between 1987 and 2000. Diagnostic sensitivity was
94 per cent for dual-phase thin-section multidetector CT,
57 per cent for dual-phase multidetector CT without thin
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268
sections and 29 per cent for sequential CT. The combination of biphasic thin-section helical CT and EUS resulted
in an overall diagnostic sensitivity of 100 per cent36 . Early
arterial phase imaging should be performed to enhance
detection (Fig. 1). However, false-negative results can
occur with pedunculated, non-hyperattenuating lesions,
or where the tumour lies adjacent to major vessels.
Recent advances in magnetic resonance imaging enable
localization of small pancreatic insulinomas (Fig. 2)50 – 52 .
Optimal detection is achieved with fast spin-echo, fat saturation and dynamic contrast-enhanced techniques with
mangafodipir53,54 . Other potentially effective new imaging
techniques include [11 C]5-hydroxytryptophan and 18 Flabelled dihydroxyphenylalanine positron emission tomography scanning55,56 .
Somatostatin receptor scintigraphy plays a central role
in locating and assessing primary gastroenteropancreatic
neuroendocrine tumours57 . However, insulinomas have
a low density of somatostatin receptors, and express
the somatostatin subtype-2 cell surface receptor in only
50 per cent of tumours58 . Consequently, somatostatin
receptor scintigraphy has a limited role in the evaluation of
primary insulinomas. Evolving techniques include peptide
receptor scintigraphy combined with anatomic imaging
methods such as CT or positron emission tomography59,60 .
In tumours that express somatostatin receptor, this can
be determined along with detailed axial imaging. This
technique has a role in tumour localization, and also
for follow-up after treatment with peptide receptor
radionuclide therapy60 .
Intraoperative imaging with intraoperative and intraduct
ultrasonography can further enhance tumour detection
Axial T2-weighted magnetic resonance imaging scan
demonstrating a well circumscribed insulinoma in the distal body
of the pancreas (arrow)
Fig. 2
rates. Intraoperative ultrasonography is done with a highresolution probe (7·5–10 MHz), allowing direct imaging
of the pancreas without the interference of overlying gas
or organs. Relevant operative anatomy can be examined
to determine the optimal resection method with respect
to proximity of the tumour to the main pancreatic duct,
combined with colour flow Doppler assessment of adjacent
major vessels (Fig. 3). Sensitivities of up to 95 per cent
are reported in the detection of pancreatic insulinomas61 .
Intraduct ultrasonography has been used to identify small
islet cell tumours, and shows promise in differentiating
benign from malignant causes of localized stenosis of the
main pancreatic duct62,63 . It uses a frequency of 20 MHz
and has a reported detection rate of over 90 per cent in the
diagnosis of 1–3-mm diameter lesions38 . However, it is not
widely available, requires specialist skills to perform and
interpret, and will probably remain confined to selected
centres.
Operative management
Axial contrast-enhanced computed tomography scan
demonstrating a well circumscribed 1·8-cm hyperechoic
insulinoma in the distal body of the pancreas (arrow)
Fig. 1
Surgical resection is the treatment of choice and offers the
only chance of cure. Overall cure rates of 75–98 per cent
are reported after surgery, with prognosis dependent on
the stage at presentation and whether complete resection
was achieved64,65 . Recent guidelines for the management
of gastroenteropancreatic neuroendocrine tumours suggest
that surgery should be confined to specialist hepatopancreaticobiliary units66 . The surgery may use laparoscopic
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269
Surgical resection of a well circumscribed insulinoma of
the distal body of the pancreas
Fig. 4
Intraoperative ultrasonography image demonstrating a
solid lesion within the pancreatic parenchyma (arrow)
Fig. 3
or open techniques, and includes enucleation, resection
and/or metastatectomy67 – 71 . Enucleation is indicated for
small, benign tumours at least 2–3 mm from the main pancreatic duct. Intraoperative ultrasonography and intraduct
ultrasonography can be used to measure the distance
between the tumour margin and the main pancreatic
duct. Macroscopically, lesions appear reddish-brown in
colour in contrast to the surrounding yellowish pancreatic parenchyma, and possess a pseudocapsule with a clear
plane of dissection between the tumour and the surrounding soft pancreatic parenchyma. Recent guidelines suggest
enucleation is enough if the lesion is clearly localized
before surgery, near or at the pancreatic surface, and easily defined intraoperatively. Histological confirmation of
complete excision and the benign nature of the insulinoma
are essential66 .
Resection is indicated when the tumour abuts the pancreatic duct or major vessels, or where malignancy is
suspected with a hard, infiltrating tumour and puckering of
the surrounding soft tissue, distal dilatation of the pancreatic duct or lymph node involvement66 . Resection options
include distal pancreatectomy, pylorus-preserving Whipple procedure, or mid-body pancreatectomy, depending
on the site of the insulinoma. A classic Kausch–Whipple
or a total pancreatectomy is rarely indicated but may
be justified in some patients66 . A spleen-preserving distal pancreatectomy (Fig. 4) is the procedure of choice
for benign or low-grade malignant distal pancreatic disease other than carcinoma72 . Patients who undergo distal
pancreatectomy and splenectomy have significantly more
postoperative complications, in particular infection, than
patients who have a spleen-preserving procedure72 . To
determine completeness of tumour excision, a perioperative insulin assay is valuable. Peripheral blood insulin levels
are measured preoperatively, during surgery and 5 min
after resection with an 8-min immunochemiluminescent
insulin assay73 . Unfortunately, this assay is not available in
most centres.
With advances in laparoscopic techniques, both laparoscopic enucleation and resection of pancreatic insulinomas have been performed successfully74 – 79 . Insulinomas
are ideally suited, as most are solitary and benign80 . A
recently reported retrospective multicentre study conducted in 25 European surgical centres demonstrated the
feasibility and safety of laparoscopic pancreatic resection
in selected patients78 . The study included 22 patients
with benign and three with malignant insulinoma, and
a variety of procedures were used, including enucleation, distal splenopancreatectomy, distal pancreatectomy
with splenic preservation and pancreatoduodenal resection. Enucleation or distal pancreatectomy was performed
in 97 per cent of patients. The overall laparoscopic conversion rate was 14 per cent, and there were no postoperative
deaths. The rate of postoperative pancreas-related complications was 31 per cent, and 6 per cent needed surgical
re-exploration. As suggested by other groups, the use
of laparoscopic ultrasonography facilitated laparoscopic
resection78,81 . Its role in the accurate localization of the
lesion, detection of proximity to vessels and the main pancreatic duct, and determination of the surgical resection
margin is often invaluable78,81 .
Intraoperative frozen section is not performed routinely
in most centres. It can provide information regarding the
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270
nature of the tissue, but is often non-diagnostic and cannot
assess features of malignancy accurately. Completeness of
excision is assessed by gross pathological appearance and
should be confirmed by formal histological examination66
(Fig. 5).
Blind pancreatic resection should not be performed
for occult insulinoma in the absence of preoperative and
intraoperative detection in the pancreas82 – 84 . In these circumstances, the surgical procedure should be terminated
and the patient referred to a specialist centre83,84 . As
insulinomas are small and the pancreatic head parenchyma
is thick, most non-palpable tumours are in the pancreatic
head. Intraoperative ultrasonography can play a critical
role in the identification of non-palpable lesions. In a
series by Norton83 , only 33 per cent of insulinomas in
the pancreatic head were palpable. However, intraoperative ultrasonography correctly identified 100 per cent of
them83 .
In 80 per cent of patients with MEN-1 who have
endogenous hyperinsulinaemia, there are multiple pancreatic tumours. In these patients, an 80–85 per cent subtotal
pancreatectomy to the level of the portal vein with enucleation of lesions in the head of the gland is recommended to
reduce the risk of exocrine and endocrine insufficiency85 .
After resection, the risk of recurrence is greater in patients
with MEN-1 (21 per cent at 20 years) than those without
MEN-1 (5 per cent at 10 years and 7 per cent at 20 years).
Malignant insulinoma
a
b
a A well differentiated pancreatic insulinoma with a
solid/nested growth pattern, psammoma bodies and a fibrous
stroma (haematoxylin and eosin stain; original magnification
×100). b Expression of insulin by neoplastic cells on
immunohistochemical staining, consistent with an insulinoma
Fig. 5
Malignant insulinomas invade locally into surrounding soft
tissue or structures, and also spread by lymph node or liver
metastases. The prognosis is determined by the stage of the
disease. Malignant pancreatic tumours are usually single
and are larger, measuring 4·7 (range 1–9) cm or more in
diameter86 . The absence of hepatic metastases is a major
predictor of survival at 3 years87 . For localized disease,
formal pancreatic resection and lymphadenectomy is
recommended87 . An aggressive approach is recommended
in the presence of metastatic disease, with concurrent
resection of the primary tumour and synchronous
hepatic metastases. Palliative resection is indicated when
preoperative evaluation shows that more than 90 per cent
of the tumour can be removed, combined with adjunctive
ablative techniques. It is also indicated for symptom relief
when best medical management fails or in the setting
of a life-threatening complication such as gastrointestinal
haemorrhage, biliary or intestinal obstruction88 . Patients
with liver metastases, those with limited metastases outside
the liver, those whose primary tumour can be controlled
and those who have a reasonable performance status are
candidates for surgical resection89 . Improved outcome
has been demonstrated in patients with metastatic islet
cell cancers managed aggressively with debulking surgery;
their overall, progression-free and symptom-free survival
rates are 71 per cent (median 76 months), 5 per cent
(median 21 months) and 24 per cent (median 26 months) at
5 years90 . Danforth et al.86 demonstrated a median diseasefree survival after curative resection of 5 years, with a
recurrence rate of 63 per cent. Palliative resection was
associated with a median survival of 4 years, compared
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with 11 months after biopsy of the tumour only86 .
Survival rates of 29 per cent at 10 years after resection
are reported4 . Conventional contraindications to surgical
resection including nodal or distant metastases, or superior
mesenteric vein invasion may need to be reconsidered in
patients with advanced neuroendocrine tumours91 .
Adjunctive techniques include hepatic arterial embolization, chemoembolization, local destruction and systemic chemotherapy92 . First-line chemotherapy includes
streptozocin-based combinations with 5-fluorouracil or
doxorubicin. Others are intensified doses of 5-fluorouracil,
dacarbazine and epirubicin93 . Total response rates
of 20–35 per cent and symptomatic improvement in
50 per cent are reported, with duration of response of
20–24 months93 . Second-line agents include interferonα and octreotide. Cisplatin and etoposide are reserved
for rapidly dividing tumours94 . Selective hepatic artery
embolization can help when systemic treatment fails, with
response rates of 50–90 per cent, and a median duration of 10–15 months. Although symptomatic response
rates of 40–90 per cent have been observed, a radiological response is seen in only 15–40 per cent. Transcatheter arterial chemoembolization, using doxorubicin
and cisplatin-based regimens, is reported to be an effective
symptomatic and antiproliferative treatment in patients
with progressive tumours95 . Patients with a tumour burden under 50 per cent and high Lipiodol (over 50 per cent)
uptake have a greater response to transcatheter arterial
chemoembolization than those with higher tumour burden. In the former group, there was a trend towards
longer survival, with 5-year survival after diagnosis of
48 per cent95 . Combination regimens of transcatheter
arterial chemoembolization and systemic chemotherapy
have resulted in higher response rates in some studies with improved survival96 . Palliative radiotherapy has
a limited role. In patients with somatostatin receptorpositive tumours, the use of radioactive isotopes combined with somatostatin analogues is well described:
111 In-labelled diethylenetriamine penta-acetate (DTPA)
octreotide and 90 Y-labelled tetra-azacyclododecane tetraacetate (DOTA) octreotide97 . Newer agents such as
radiolabelled arginine-glycine-aspartate-DTPA-Tyr3 and
177 Lu-labelled DOTA0 -Tyr3 octreotate have recently
been reported98,99 . Local ablation techniques for liver
metastases include alcohol injection, cryotherapy and
radiofrequency ablation.
Medical management
Medical management of insulinoma is generally restricted
to patients with unresectable metastatic disease, high-risk
271
candidates for surgery, those not suitable for resection
or in those who have undergone an unsuccessful
operation with persistent symptoms. Options include
dietary management, diazoxide, calcium channel blockers
and somatostatin analogues. Patients are advised to
avoid prolonged fasting and to take frequent meals and
snacks, including complex carbohydrates. Diazoxide is an
antihypertensive drug with hyperglycaemic effects100 . It
acts directly on β cells suppressing insulin secretion, and
enhances glycogenolysis. The recommended daily dose is
200–600 mg orally. Good symptom control is achieved in
about 50 per cent of patients. However, significant sideeffects of oedema, weight gain, hirsutism and nausea
are common. The calcium channel blocker, verapamil,
has also been used with some success101 . Octreotide, a
synthetic somatostatin analogue results in only temporary
and modest symptom relief. It can worsen hypoglycaemic
symptoms owing to a greater suppressive effect on growth
hormone and glucagon secretion than on insulin. A
satisfactory response is reported in only 50 per cent of
patients. Novel therapeutic approaches in the treatment of
neuroendocrine tumours have been described, including
inhibition of the epidermal growth factor receptorsensitive tyrosine kinase by gefitinib102 .
Conclusion
Insulinomas are uncommon tumours. Most are intrapancreatic, benign and solitary. Non-invasive preoperative
imaging to localize the lesion continues to evolve. Recent
guidelines for the management of gastroenteropancreatic neuroendocrine tumours recommended a multimodal
approach to detect primary tumours, which may include
CT, somatostatin receptor scintigraphy, EUS, and in some
centres selective arterial calcium stimulation with hepatic venous sampling66 . A biochemical diagnosis obtained
during a supervised 72-h fast followed by high-quality
dual-phase thin-section multidetector CT of the pancreas confirms the diagnosis and localizes the insulinoma
in most patients. Further evaluation by EUS is valuable
for insulinomas in the proximal pancreas. Other imaging
methods may be reserved for patients with negative CT.
Preoperative imaging combined with intraoperative ultrasonography should enable accurate tumour localization
in more than 95 per cent of patients, and blind pancreatic resection in the absence of tumour detection is not
recommended. Laparoscopic enucleation is increasingly
performed, and leads to long-term cure if the tumour is
benign. Aggressive debulking surgery may benefit patients
with metastatic insulinoma, particularly if they are young
and fit for surgery.
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272
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The management of insulinoma O. N. Tucker , P. L. Crotty

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