Surgical treatment of insulinomas * Emily Finlayson, MD , Orlo H. Clark, MD

Surg Clin N Am 84 (2004) 775–785
Surgical treatment of insulinomas
Emily Finlayson, MDb, Orlo H. Clark, MDa,b,*
a
Department of Surgery, University of California,
San Francisco, 513 Parnassus Avenue S-320 San Francisco, CA 94143-0104, USA
b
Department of Surgery, University of California, San Francisco Comprehensive Cancer
Center at Mount Zion Medical Center, 1600 Divisadero Street, Hellman Building,
Room C3-47 San Francisco, California 94143-1674, USA
Insulinoma, with an annual incidence of 1 to 4 per million, is the most
common islet cell tumor [1]. Most patients present with sporadic disease, and
the median age at presentation in this population is 47 years. The vast
majority of insulinomas in patients with nonfamilial disease are small (90%
less than >2 cm), solitary (90%), and benign (90%). Unlike other
pancreatic neuroendocrine tumors, they arise with equal frequency throughout the gland. They occur twice as often in women. Nearly 10% of tumors are
associated with multiple endocrine neoplasia (MEN) type 1. In this context,
multiple islet cell tumors are usually present.
Although it has been over 7 decades since the first surgical cure of
insulinoma [2], diagnosis, localization, and surgical therapy remain challenging and controversial. Recent advances in preoperative and intraoperative
radiologic localization have improved the ability to identify insulinomas
preoperatively and intraoperatively, and have resulted in superior surgical
cure rates [3,4]. In addition, the emergence of laparoscopic approaches for
benign pancreatic lesions may offer a less invasive option for selected patients
with insulinomas. In this article, we discuss clinical presentation and
diagnosis of insulinomas, controversies in preoperative and intraoperative
localization, and the role of the laparoscopic approach.
Diagnosis
Clinical presentation
Patients with insulinoma present with symptoms of hypoglycemia—lightheadedness, altered mental status, and abnormal behavior. Symptoms
* Corresponding author.
E-mail address: clarko@surgery.ucsf.edu (O.H. Clark).
0039-6109/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.suc.2004.02.004
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generally occur after a fast—in the morning, after skipping a meal, or after
exercise. Because symptoms of insulinoma are primarily behavioral, patients
are often misdiagnosed and definitive diagnosis is delayed. In our institution,
the duration of symptoms before diagnosis ranged from 1 hour to 34 years,
with a mean of 3.8 years [5].
Diagnostic tests
Traditionally, the diagnosis of insulinoma is suggested by the presence of
Whipple’s triad—serum glucose \45 when symptomatic, symptoms of
hypoglycemia with fasting, and symptom relief with glucose. Additional
laboratory tests can help confirm the diagnosis. Serum insulin levels greater
or equal to 6 microunit/mL and a plasma insulin-to-glucose greater than 0.3
are diagnostic of insulinoma. In patients with borderline-fasting insulin
levels, measurement of proinsulin levels is useful. Proinsulin levels in patients
are substantially elevated—ranging from 30 to 2300 pmol/L [6]. In addition,
the molar ratio of proinsulin to insulin is higher in patients with
insulinoma—1:6 in healthy subjects versus 1:1 in patients with insulinoma.
Measurement of C-peptide levels is useful in confirming the diagnosis of
insulinoma. C-peptide, which is secreted in equimolar amounts as insulin by
beta cells, is an accurate marker for endogenous insulin secretion. C-peptide
levels of 2 nmol/L or greater suggest the presence of an insulinoma. Normal
C-peptide levels in the setting of elevated blood glucose levels and
hyperinsulinemia raise the question of accidental or surreptitious use of
insulin or sulfonylureas. This etiology of hypoglycemia and hyperinsulimenia
should be entertained in all patients, and especially in patients with access to
hypoglycemic medications, such as health-care workers and family members
of people with diabetes mellitus. Measurement of plasma or urine
sulfonylureas excludes this diagnosis.
Determination of plasma insulin and glucose levels is most reliably
obtained through an observed, in-patient fast. Patients are fasted, and plasma
levels of glucose, insulin, and c-peptide are measured every 6 hours. When
plasma glucose levels fall to 40 mg/dL or symptoms of hypoglycemia develop,
the fast is terminated. A substantial proportion of patients—33%—become
hypoglycemic within 12 hours, 65% within 24 hours, 84% within 36 hours,
93% within 48 hours, and 99% within 72 hours [7]. Increasingly, outpatient
overnight fasts with next-day testing in an ambulatory center are replacing
inpatient 72-hour fasts. Up to 40% of patients have positive fasts in this
setting [7]. The remaining patients will require hospital admission for the
completion of the study.
Although a 72-hour fast is diagnostic in the majority of patients with
insulinoma, additional tests are available to confirm the diagnosis. The Cpeptide suppression test involves the infusion of exogenous insulin to suppress
endogenous insulin secretion. In healthy subjects, when hypoglycemia is
induced by exogenous insulin, endogenous insulin (measured as C-peptide
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777
secretion) is suppressed by 50% to 70%. Elevated C-peptide after insulin
infusion suggests the presence of insulinoma. Tolbutamine, a secretagogue
that stimulates insulin secretion from insulinomas, can also be used to test for
the presence of an insulinoma. In a tolbutamide tolerance test, plasma glucose
levels less than 47 mg/dL or insulin levels greater than 20 microU/mL suggest
the diagnosis of insulinoma.
Preoperative localization
Noninvasive imaging
Results of noninvasive localization studies for insulinoma are often
disappointing. Because of their small size (generally about 1 cm), transabdominal ultrasound (US), computed tomography (CT), and magnetic
resonance imaging (MRI) often fail to demonstrate the tumor. Transabdominal ultrasound is highly operator-dependent, and tumor localization
rates vary widely, from 13% to 67% [8]. In published series, CT scanning
successfully localizes insulinomas in 17% to 73% of patients [4,5,8–15]. Even
lower localization rates for have been demonstrated for MRI: 7% to 45%
[4,5,8,11,16]. Although both MRI and CT scanning are of limited value for
localization, these imaging studies give essential information about the
presence or absence of metastatic disease, and also identify patients with large
malignant tumors, which helps with preoperative planning. Somatostatin
receptor scintigraphy is often useful for localizing many other pancreatic
endocrine tumors; however, it usually fails to demonstrate insulinomas [10].
Because most insulinomas do not express type 2 somatostatin receptors, only
about 30% bind octreotide.
Invasive imaging
When preoperative noninvasive studies fail to localize tumors in patients
with the biochemical diagnosis of insulinoma, invasive studies are often more
successful. Endoscopic ultrasound (EUS) is rapidly becoming the diagnostic
modality of choice for tumor localization. Numerous studies have reported
superior localization rates with EUS [14,16–19]. With reported localization
rates of 70% to 90%, many advocate it as the study of choice for
identification of insulinomas; however, because of the anatomic relationship
between the stomach and the pancreas, the sensitivity of EUS varies by tumor
location. In Schumaker et al’s series, localization rates were substantially
lower for tumors in the distal pancreas—37% for insulinomas of the distal
pancreas versus 83% for insulinomas in the pancreatic head [20]. An
additional limitation is that EUS is highly operator-dependent and is not yet
widely available. Most published series are conducted at referral centers.
Whether EUS is as successful in all hands is unknown.
Historically, selective pancreatic angiography was the study of choice
for localizing insulinomas. Reported localization rates for angiography,
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however, vary widely, ranging from 27% to 80% [9,11,19,21–28]. Because of
its cost, invasiveness, and relatively low sensitivity, arteriography is no longer
a first-line localization study for insulinoma. It still has a role, however, in
selected patients with persistent or recurrent disease in whom other localizing
studies have been equivocal or negative.
Regional localization of insulinomas can be facilitated by transhepatic
portal venous sampling (PVS). In this procedure, the portal vein is
catheterized percutaneously and the catheter is advanced into the small veins
draining the pancreas. Plasma insulin levels are obtained from each region of
the pancreas to determine the location of the tumor. Localization rates for
PVS range from 67% to 100% [4,5,9,12,21,25–27]. Selective arterial calcium
stimulation with hepatic-vein catherization (the Imamura-Doppman test) has
largely replaced PVS. In this procedure, the splenic, superior mesenteric, and
gastroduodenal arteries are selectively catheterized. Calcium—a secretagogue for insulinomas—is sequentially injected into each artery. Venous
samples of insulin, glucose, and calcium are then obtained from the right
hepatic vein after each calcium infusion to localize the tumor. This procedure
has a higher sensitivity for regional localization of insulinomas than
PVS—91% to 100% [11,12,28]. Both PVS and selective arterial calcium
stimulation are invasive and expensive. For this reason these modalities, like
arteriography, are now used primarily for patients with persistent or
recurrent disease.
Surgical approaches
Operative technique
Surgical cure rates in patients with the biochemical diagnosis of
insulinoma range from 77% to 100% [4,26,29,30]. At surgical exploration,
the abdomen is initially explored for evidence of metastatic disease. The lesser
sac through the gastro-collic ligament is then entered to expose the anterior
surface of the pancreas. To facilitate bimanual palpation of the head of the
pancreas, a Kocher maneuver is performed to mobilize the duodenum and
head of the pancreas. Intraoperative palpation has been shown to be a reliable
method for localizing insulinomas—with successful identification of 42% to
95% of tumors [4,5,9,12,27,31].
Perhaps the most sensitive technique for intraoperative tumor localization
is intraoperative ultrasound (IOUS). In published series, it successfully
localizes 75% to 100% of insulinomas [4,5,9,11,12,27,30–32]. Because the
combination of palpation and IOUS is very effective method of intraoperative
tumor localization, many now argue that expensive, invasive preoperative
localization studies are not necessary, and should only be used for patients
with persistent or recurrent disease [30,32]. IOUS is also useful in determining the relationship between insulinomas, and their relationships to the
pancreatic duct and vessels. Identification of the pancreatic duct and
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779
determination of its proximity to the tumor can guide safe enucleation of
the tumor. This approach can minimize the likelihood of a postoperative
pancreatic fistula.
Tumor enucleation, when feasible, is the technique of choice. Using Bovie
electrocautery, the tumor is carefully dissected away from the normal
pancreatic parenchyma. Various maneuvers can be used to decrease the risk
of pancreatic leak. For small insulinomas, the pancreatic capsule can be
closed over the defect. The application of fibrin glue to the defect may also be
another useful tool. There is recent evidence that the use of fibrin glue can
decrease the incidence of pancreatic fistula after pancreatic surgery [33,34].
Although most insulinomas are solitary, steps should be taken intraoperatively to ensure that additional disease is not missed. As many as 20%
of patients with hyperinsulinemia have multiple tumors or nesidioblastosis
(Fig. 1A, B) [35,36]. The latter is rare in adults but more common in neonates.
The entire pancreas should be mobilized and palpated. If available, IOUS
should be used to inspect the length of the pancreas gland. Rapid immunoreactive insulin (IRI) assays can confirm complete resection of insulinomas
Fig. 1. (A) ‘‘Single insulinoma’’ (patient with sporadic islet cell tumor of pancreas). (B)
Multiple islet cell tumors in patient with MEN1, hypoglycemia, and insulinoma. (Note: Should
read MEN [the number one]).
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intraoperatively. For this test, serum insulin levels are drawn from the portal
vein and a peripheral vein at the beginning of the procedure. Twenty minutes
after resection of the tumor, repeat portal and systemic insulin levels are
drawn. Insulin levels are expected to decrease to the normal range, and
insulin/glucose ratios should be less than or equal to 0.4 within 20 minutes of
successful insulinoma resection. Studies of the use of IRI measurement to
predict operative cure have reported sensitivity of 84% to 100% and accuracy
of 84% to 89% [35,37]. Blood sugar levels also begin to increase in most
patients within 15 minutes of removal of an insulinoma. In very thin patients,
the increase in blood sugar levels make take longer.
Historically, blind distal pancreatectomy was the procedure of choice
when insulinomas were not identified intraoperatively. It was thought that
because insulinomas are distributed evenly throughout pancreas, a distal
pancreatectomy would cure many patients with occult tumors. In a recent
review of 17 patients referred to the National Institutes of Health (NIH) after
failed blind distal pancreatectomy, 5 were diagnosed as having factitious
hypoglycemia, and in the remaining 12 the tumor was localized in the
pancreatic head [8]. To preserve pancreatic function and reduce the risk of
iatrogenic diabetes mellitus, patients in whom tumor localization is
unsuccessful at operation should be carefully evaluated to be certain of the
diagnosis, and in general should not undergo blind resection. Instead, these
patients should be referred to an experienced endocrine endocrinologist or
surgeon for confirmation of the diagnosis and further localization studies.
Laparoscopy
Recent advances in laparoscopic technique and instrumentation have
enabled surgeons to approach complex procedures laparoscopically. Over the
past decade, there have been numerous case reports or small series of
successful laparoscopic resections of insulinomas [38–47]. The pancreas is
exposed in the standard fashion. Laparoscopic ultrasound can be used to
identify nonvisible tumors and determine the relationship of the lesion to
surrounding veins and the pancreatic duct. Laparoscopic ultrasound can be
particularly helpful in identifying lesions of the tail that are often missed by
endoscopic ultrasound [48]. For superficial ventral tumors, laparoscopic
enucleation is undertaken with electrocautery or laparoscopic coagulating
shears (Harmonic scalpel, Ethicon, Somerville, New Jersey). Small pancreatic
feeder vessels can be either clipped or cut with the LigaSure device (Tyco, U.S.
Surgical, Norwalk, Connecticut). Tumors located deep in the body or tail of
the pancreas and those in close proximity to the pancreatic duct require distal
pancreatectomy. In cases where visualization and ultrasound fail, a hand port
can be used to allow palpation of the gland. Tumors situated very distally in
the splenic hilum are especially difficult to identify. Spleen-sparing distal
pancreatectomy can be accomplished by careful division of the short gastric
vessels and stapling of the pancreas.
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781
Results of laparoscopic resection for insulinoma have been mixed. Tumors
are sometimes difficult to identify, because one cannot palpate the increased
firmness of the tumor, and tumor color is often less helpful for identifying the
tumor. Avoidance of laparotomy should translate into shorter recovery
times. Hospital stays in reported series, however, are relatively long—ranging
from 2 days to 14 days [38–45,47]. Mean operative time ranges from 1.7 hours
to 5 hours [38–45,47]. Pancreatic fistula rates are comparable to those for
open procedures. Open insulinoma resection is associated with a pancreatic
fistula rate up to 43% [29]. Fistula rates for laparoscopy ranged between 0%
to 40% [40,44,47], with one patient requiring reoperation. [40] These high
fistula rates underscore the need for intraoperative drain placement after
laparoscopic resection to facilitate the diagnosis and treatment of pancreatic
leaks. Finally, conversion to an open procedure is reported as high as 33% to
40% [39,44]. As with many emerging laparoscopic techniques, there is
a necessary learning curve. In our experience with laparoscopic resection,
which we have only used in patients who have their tumors identified
preoperatively, the duration of hospitalization has been shorter by 1 to 3 days
than after open procedures, and subsequent return to full activity is faster.
Special circumstances
Multiple endocrine neoplasia
Over 75% of patients with multiple endocrine neoplasia (MEN) type 1
present with multiple insulinomas and other, often nonfunctioning islet cell
tumors [49]. For this reason, patients presenting with hypoglycemia and
hyperinsulinemia should be carefully screened for MEN type 1. Patients with
MEN type 1 often have a family history of endocrinopathy, hypercalcemia,
or a history tumors of the parathyroid or pituitary. Because insulinomas in
these patients are usually multicentric, local tumor resection often results in
disease recurrence [50]. Subtotal pancreatic resection with IOUS-guided
enucleation of pancreatic head lesions is the procedure of choice for
hyperinsulinemia in patients with MEN type 1 [49,50]. In contrast to
gastrinomas, virtually all insulinomas (99%) are situated in the pancreas.
Nesidioblastosis
Nesidioblastosis is a rare but important cause of hypoglycemia and
hyperinsulinemia in adults. Also known as endocrine cell dysplasia, islet cell
hyperplasia, islet cell hypertrophy, islet hypertrophy, microadenomatosis,
and neisidiodysplasia, it is characterized by diffuse hyperplasia of the
pancreatic islet cells. Although it is the most common cause of hyperinsulinemia in neonates, and is not uncommon in young children, it is rarely
diagnosed in adults. Preoperative studies can sometimes help in distinguishing nesidioblastosis from insulinoma. Negative preoperative diagnostic or
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intraoperative localization procedures should raise the suspicion of
nesidioblastosis. In this situation, intra-arterial calcium angiogram can be
used. If insulin levels rise after each selective calcium injection, multicentric
insulinoma or nesidioblatosis are the likely diagnoses.
Surgical management of adult-onset nesidioblastosis is controversial. In
case reports of surgical management of adult nesidioblastosis, surgical
approach included 70% to 95% distal pancreatectomy [51–56]. Although
near-total pancreatectomy is associated with the chance for cure for
hyperinsulinemia, it carries a high risk of subsequent development of
insulin-dependent diabetes—up to 40%. This is also true in children
immediately after near-total pancreatectomies or subsequently at adolescence. In the largest case series (n = 5), patients underwent 70% distal
pancreatectomy [56]. Of these patients, three remained asymptomatic and
two had recurrent hypoglycemia.
Summary
Insulinoma should be included in the differential diagnosis of all patients
presenting with hypoglycemia. A plasma insulin-to-glucose level greater than
0.3 and C-peptide levels of 2 nmol/L or greater suggest the presence of an
insulinoma. CT scan of the abdomen is useful as a initial imaging study to
exclude metastatic disease and for identifying uncommon large islet cell
tumors, but has poor sensitivity for localizing most insulinomas. Transgastric
endoscopic ultrasound has emerged as the most sensitive preoperative
localizing technique. The combination of palpation and intraoperative
ultrasound identifies nearly all tumors at the time of operation, and gives vital
information about surrounding structures. If no tumor is found intraoperatively, blind distal pancreatectomy should not be performed, and the
patient should be referred to an experienced endocrinologist or endocrine
surgeon for confirmation of the diagnosis and further localization studies.
Laparoscopy is emerging as a viable alternative to open tumor resection.
Successful resection—both enucleation and distal pancreatectomy—has been
reported over the past decade. Intraoperative use of laparoscopic ultrasound
can facilitate localization and guide safe resection.
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