Preoperative Endoscopic Ultrasound (EUS) Imaging in Diagnosis of Insulinomas
in a University Hospital in Damascus
Hazem B. Aljasem1 & Zaynab. Alourf*2
1Faculty of Medicine, Department of Surgery. Damascus University, Damascus, Syria
2Faculty of Medicine, Department of Internal Medicine. Damascus University, Damascus, Syria
Abstract Introduction :
Endoscopic ultrasound (EUS) is a very important procedure to preoperatively localize insulinomas and plan the surgery.
This end with less time and less invasive surgical approach. However, under optimal conditions, about 10-20% of insulinomas are
missed even by experts. The purpose of this retrospective study was to recognize factors that could affect EUS results.
Methods: This study was carried out at Al-Assad University Hospital (AUH), Damascus, Syria. Eighteen patients fulfilled the inclusion
criteria ( positive 72 hours fasting test and successful surgery with histopathology confirmation). All EUSs were performed by one experienced examiner.
Results: All 18 cases were benign insulinomas (16 were tumors and two were hyperplasias). Preoperative EUS did not detect six tumors (negative EUS). They were all isoechoic to surrounding normal pancreatic tissue. The ten detected cases (positive EUS = 62.5%) were
hypoechoic, isoechoic or hyperechoic lesions. Positive EUS patients were younger than negative EUS patients (P =0.05). The mean tumor diameter in positive EUS was significantly larger than negative EUS (P =0.04).
Conclusion: Some Isoechoic Insulinomas were not detected by EUS imaging. Smaller tumor diameter and older age of the patient might be behind negative imaging.
Keywords: Preoperative Diagnosis, Insulinoma, Endoscopic Ultrasound, EUS
Insulinomas are endocrine pancreatic beta cells tumors. Even
though they are rare, insulinomas are the most common
functioning islet cell tumor of the pancreas. Their incidence
is about one in 250,000 patient/year (Cryer, 2008; Hoem,
2008). Patients are almost always cured lifelong with complete
elimination of a benign insulinoma (Grant, 2005). Mehrabi et al,
in 2014, carried out a systematic review for 114 articles with 6222
cases of insulinoma. They reported that patients with insulinomas
are mostly in their fifties, with a higher incidence in men. In
conclusion they found that insulinomas are mostly sporadic
(94%), benign (87%), and single (90%) (Mehrabi A, et al. 2014).
About 10% of insulinoms are part of Multiple endocrine neoplasia
type 1 (MEN-1) (Thakker RV, et al, 2012; Carroll RW, 2013). Inhospital
watched full prolonged (72h) fasting test is the confirming
diagnostic test of insulinoma with an accuracy of approximately
100% (Kann PH, et al, 2007). After that, it is mandatory to localize
insulinoma by imaging procedures. These are non-invasive such
as abdominal sonography, magnetic resonance imaging (MRI),
computed tomography (CT), and the scintigraphy of somatostatin
receptors. Other procedures are invasive such as preoperative and
intra-operative endoscopic ultrasound (EUS). However, all these
methods have low sensitivities (Müller et al, 1994; Zimmer T, et
al, 2000; Kann P & Zielke A, 2005; Kaczirek K, et al, 2004).
The intra-operative EUS is more accurate and could improve the
detection of pancreatic tumor (near 100%) (Chung JC, et al, 2006).
Since 1990s EUS has been considered the reference method in localizing insulinomas with using a high-frequency sonography
probe, that can get very close to the pancreas ( Kann P 2016,
McLean, A. M. and Fairclough P. D, 2005; Nesje LB, et al, 2002).
Preoperative EUS helps in surgical planning to end with minimal
invasive approach in shorter time. This because it precisely
localize the tumor and its relation to vital structures (vessels, bile
and pancreatic duct), in addition to determine whether the disease
is uni- or multifocal (Fendrich V, et al, 2004; Langer P, et al, 2005;
Kann P, et al, 2001; Kann P, 2006). It could also distinguish benign
from malignant lesions and confirm that by guided fine needle
aspiration (Gornals J, et al 2011; Leelasinjaroen P et al, 2014).
EUS detection rates ranged between 86.6% and 93% (Okabayashi
T, et al, 2013; Tavcar I, et al, 2014). In 2015, Tellez-Avila et
al reported that EUS sensitivity, positive predictive value, and
accuracy are 100 %, 95.4 %, 95.4 % respectively. Despite this,
10-20% of insulinomas cannot be diagnosed by EUS, even with
experienced examiners and under optimal conditions (Tellez-Avila
et al 2015 , Kann P & Zielke A, 2005; Mirallie E, et al, 2002).
Above and beyond examiner’s experience, many factors that might
affect EUS outcome were reported . First, different devices have
different accuracies (i.e. higher frequency in MHz gives higher
accuracy) (Bhutani, Deutsch, 2010). Second, EUS should be done
under standardized conditions (like sedation and positions of the
patient). Finally, there might be factors that are related to patients;
Kann et al, reported that low body mass index, female gender, and
young age are associated with negative EUS (Kann P, et al, 2007).
The purpose of this study was to recognize factors that might affect
EUS imaging in patients with pancreatic insulinomas. This could
help in finding new ways or techniques to avoid false negative
results. There is no such study in Syria.
Materials and Methods:
This retrospective study was carried out at Al-Assad University
Hospital (AUH) in Damascus, Syria. Inclusion criteria were: a
positive 72 hour fasting test, preoperative EUS imaging, successful
surgery and histopathology.
72h fasting test protocol in AUH: No food intake but patient is
allowed to drink calorie-free and caffeine-free beverages. Blood
specimens are collected for measurement of blood glucose every
six hours until the glucose concentration is below 60 mg/dL (3.3
mmol/L); at this point, the frequency of sampling is increased
to once every one to two hours. The test is ended when blood
glucose concentration is ≤45 mg/dL (2.5 mmol/L), the patient has
symptoms or signs of hypoglycemia, or when the blood glucose
concentration is less than 55 mg/dL (3 mmol/L) if Whipple’s
triad (hypoglycemic symptoms that improved with eating) was
documented on a prior occasion. Blood specimen is collected
before allowing the patient to eat for blood glucose, insulin,
C-peptide, and cortisol (to rule out adrenal insufficiency)
72h fasting test is positive when insulin-glucose ratio is > 0.25
(Wiesli P, et al, 2002). Exploratory surgery may be established
after positive 72h fasting test even if all of the other diagnostic
procedures were negative.
All EUSs were done by the same expert examiner using the same
device, OLYMPUS EndoEcho (EU-C 2000 endosonoscope) with
OLYMPUS UWS-1water supply unit (for ultrasonic endoscope),
and OLYMPUS OEV181H high definition monitor.
The patients were positioned in the left decubitus and under
conscious sedation. Fiberscope is inserted as far as the second
portion of the duodenum in oblique-viewing with the transducer
located at the tip of the fibroscope. Scanning was performed
with de-aerated water filled balloon applied to the tip of the
echoendoscope. Primarily, pancreatic head was scanned for
exploration of the entire head of the pancreas, the instrument
was straightened in the same way as endoscopic retrograde
cholangiopancreatography (ERCP). The probe was adherent to the
duodenal wall. If the insertion depth of the instrument was correct,
the pancreatic head and the uncinate process could be seen. Then,
the endoscope was drawn backwards to the stomach and scanning
of the rest of the pancreas was performed. The pancreas was
scanned longitudinally in a craniocaudal direction with clockwise
rotation and slight retraction of the scope towards the spleen then
the pancreatic body and tail were imaged (Dietrich, 2006).
The following information were extracted from patients records,
EUS, surgical and histopathology reports: gender (female/male),
age, body mass index BMI (kg/m2) (four were missing), largest
tumor diameter (mm, taken from preoperative EUS imaging,
and from the report of histopathology if EUS negative) (one was
missing), the histopathology of tumor (benignancy/malignancy),
fasting test, highest ratio: insulin serum concentration (µU/ml)/
blood glucose (mg/dl) (during hypoglycemia in the 72h), and
echognicity of tumor (hypo-/iso-/hyperechoic).
SPSS 18 software (SPSS Inc, Chicago, IL, USA) was used for
statistical analysis. Nonparametric tests (Mann-Whitney Test for
continuous variables) were used because of the small sample size
(non-normal distribution). Chi-square test was used for categorical
variables. Statistical significance level: P ≤ 0.05 was considered
significant. Results were reported as means and standard deviation
130 records with different causes of hypoglycemia between 2006
and 2012 were systematically reviewed. 20 patients of them (15%)
were diagnosed with insulinomas. However, 18 of them fulfilled
the inclusion criteria. Two were pancreatic hyperplasia (11%) and
16 were tumors (five males and 11 females) (Table 1). Hyperplastic
lesions were excluded as they cannot be discovered by EUS (false
Of the 16 subjects, 10 (62.5%) were EUS positive, 6 (37.5%) were
EUS negative (Fig. 1). EUS positive and EUS negative groups
were similar in respect to gender (70% female vs. 67% female,
respectively). The EUS positive group was found to be younger
in age than the EUS negative group (25.0 ± 11.7 years vs. 37.8 ±
11. 6 years, respectively; p = 0.05). The EUS negative group had
a smaller mean tumor diameter than the EUS positive group (9.4
± 3.8 mm vs. 15.2 ± 5.3 mm, respectively; P=0.04). There was no significant difference observed between EUS positive and negative
groups when it came to insulin-glucose ratio (2.06 µU/ml per mg/
dl vs. 0.72 µU/ml per mg/dl, respectively) or BMI (26.3 kg/m2 ±
2.8 kg/m2 vs. 27.8 ±10.2 kg/m2, respectively) (Table 2).
Binary logistic regression (detection as dependent, age and tumor
size as covariates) reveals no significance.
Our study showed that smaller tumor diameter and older age of
patient might affect EUS detection ability and end with negative
result. It is reasonable that the larger the tumor diameter the higher
the chance of detection. The echognicity of the pancreas increases
with age beginning at the 4th decade of life which means that
the pancreas echognicity is higher than the liver’s (Glaser J, et
al, 2000). Increasing age or obesity leads to a uniform increase
in echogenecity that is referred to as pancreatic lipomatosis this
greatly increase the contrast to anechoic splenic vein and the
confluence of the portal vein. Pancreatic tumors are often more
hypoechoic than the rest of the parenchyma and are difficult to
be distinguish from adjacent bowel loops or peripancreatic lymph
nodes. This might explain the tendency to have negative EUS in
Our results did not match with Kann et al results which reported
that low body mass index, female gender, and young age all
associated with negative EUS. These differences between our study
and theirs might be explained by three reasons. First, they have a
larger sample size than ours (29 patients vs. 16). Second, different
devices and examiners might end with different results. Finally,
while our patients were lying on the left side, their patients were in
supine position. The former position of patient might give negative
EUS, because the transducer of the fibroscope might go to a more
lateral position by sliding over the pancreas. Some studies reported
that repeating EUS with a supine position might make negative
EUS positive. Because small sample size is the main limitation,
further studies are warranted to be carried out with a larger sample
size. Being a retrospective study is another limitation. Prospective
study considering these risk factors (which we concluded) and
changing position to the supine one in case EUS with left position
is negative, might end with different results.
The authors wish to thank Faculty of Medicine,
Damascus University and AUH for ethical approval. They also
thank Dr. Muhammad Rafat B. Meda and Dr, Mohamad Emad S.
Abdulrhman for assistance in data collecting. They appreciate
Miss Hend Alkabbani, and all members of medical record
department at AUH for their help.
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