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Review Article
Chirurgia (2019) 114: 550-563
No. 5, September - October
Copyright© Celsius
http://dx.doi.org/10.21614/chirurgia.114.5.550
550 www.revistachirurgia.ro Chirurgia, 114 (5), 2019
Rezumat
Cazurile de cancere digestive diagnosticate în timpul sarcinii sunt
rare, raportarea lor fiind sporadică. Deplasarea gravidităţii spre
intervalul de vârstă ‘30-39 de ani (şi deloc excepţional 40-49 ani) ar
putea explica suprapunerea din ce în ce mai frecventă a cancerelor
şi sarcina. Tumorile pancreatice de tip NET (PNET) au origine în
ţesutul endocrin insular, fiind entităţi extrem de rare, având
caracteristic un comportament de dezvoltare neoplazică lent, puţin
agresive, cu capacitatea de a secreta şi înmagazina diferite peptide
şi neuroamine. Din grupa mare a tumorilor de tip NET, cca 70 %
sunt localizate gastro-entero-hepatic (GET) şi reprezintă mai puţin
de 2% din tumorile tubului digestiv. Incidenţa PNET este extrem
de redusă cca 1/100.000. În literatură, asocierea sarcină-PNET este
excepţională, fiind raportate până la acest moment 39 astfel de
cazuri. Cea mai frecventă PNET raportată la gravide este
insulinomul, pînă în 2012 fiind publicate 27 de cazuri la nivel
global, cu punct de dezvoltare în celulele β-pancreatice, dintr-un
total de 39 cazuri de PNET descrise. Diagnosticul la gravide este
îngreunat în prima parte a sarcinii deoarece, din punct de vedere
fiziologic, în această perioadă glucoza are tendinţa să aibă nivel
scăzut, consecinţă a secreţiei crescute de insulină şi a sensibilităţii
la insulină, probabil ca efect al creşterii nivelului de estrogeni. De
asemenea, şi alte semne care ar putea sugera prezenţa unei
”probleme”, cum ar fi astenie neexplicată, vărsături, hipotensiune,
episoade reduse de hipoglicemie, sunt relativ comune în primul
trimestru de sarcină. Dificilă este şi evaluarea paraclinică a
acestor paciente, un indicator important al oportunităţii unei
Pancreatic Neuroendocrine Tumour in Pregnancy
- Diagnosis and Treatment Management
Dragoæ Predescu
General and Esophageal Surgery Department, Center of Excellence in Esophageal Surgery, Sf. Maria Clinical Hospital, Bucharest, Romania
Corresponding author:
Dragoæ Predescu MD
General and Esophageal Surgery
Department, Center of Excellence
in Esophageal Surgery, Sf. Maria
Clinical Hospital, Bucharest
37-39 Bdul Ion Mihalache, sector 1
Bucharest, Romania
E-mail: drpredescu@yahoo.com
Received: 04.08.2019
Accepted: 07.09.2019
Abbreviations:
PNET - Pancreatic Neuroendocrine
Tumours;
GET - Gastroenterohepatic;
VIP - Vasoactive Intestinal Polypeptide;
EUS - Endoscopic Ultrasound;
EGD - Esophagogastroduodenoscopy;
CT - Computed Tomography;
MRI - Magnetic Resonance Imaging;
MEN - Multiple Endocrine Neoplasia.
Pancreatic Neuroendocrine Tumour in Pregnancy - Diagnosis and Treatment Management
Chirurgia, 114 (5), 2019 www.revistachirurgia.ro 551
investigaţii sau alteia revenind trimestrului de graviditate. Precauţia legată de ”compromiterea”
fetală în indicarea unei explorări invazive (imagistice, endoscopice, etc) întârzie de asemenea
diagnosticul. Caracterul puţin agresiv, mai de curând cu potenţial benign face ca prognosticul
insulinoamelor să fie în general unul favorabil iar posibilităţile terapeutice uşor de administrat şi
controlat la gravide. Tratamentul medical se adresează pacientelor atunci când există diagnostic
pozitiv dar nu putut identifica topografia insulinomului, când simptomatologia este uşor controlată
prin terapie conservatoare până când se obţine o vârstă convenabilă a fătului fie imediat post-
partum, la gravidele care refuză intervenţia chirurgicală, fie în stadiul metastatic al insulinomului
malign. Tratamentul chirurgical rămâne cu adevărat singura modalitate de rezolvare terapeutică
dar, cel mai adesea, sub forma unei chirurgii programate, de regulă post-partum, sau dacă situaţia
”forţează” indicaţia, cât mai târziu după o vârstă fetală convenabilă (după 28 săptămâni).
Cuvinte cheie: neoplazia neuroendocrinã pancreaticã, sarcinã, managementul de diagnostic şi
tratament
Abstract
Digestive cancers diagnosed during pregnancy are rare and are sporadically reported. The shift
of pregnancy towards the age interval of 30-39 years old (and even 40-49 years old) could explain
the more and more frequent superposition of pregnancy and cancer. Pancreatic Neuroendocrine
Tumours (PNET) originate in the insular endocrine tissue and are extremely rare; they have a
slow, less aggressive neoplastic development, with the capacity of secreting and storing different
peptides and neuroamines. From the large group of NET tumours, approximately 70% have a
gastroenterohepatic (GET) localisation and represent less than 2% of the digestive tract
tumours. PNET incidence is extremely reduced, of approximately 1/100.000. The association of
pregnancy and PNET in literature is exceptional until now only 39 cases were reported. The
most frequent PNET in pregnant patients is the insulinoma with the starting point in
pancreatic β-cells, with 27 out of 39 PNET worldwide reported cases until 2012. Establishing a
diagnosis in pregnant patients is difficult in the first period of pregnancy because physiologically,
the glucose tends to be low. This may be a consequence of the increased secretion of insulin and
sensibility to insulin, probably as an effect of increased oestrogen levels. Furthermore, there are
other signs which could suggest the existence of a “problem”, which are relatively common
during the first trimester of pregnancy: unexplained fatigue, vomiting, hypotension, rare
episodes of hypoglycaemia. Performing paraclinical tests on these patients is difficult; an essential
indicator of the opportunity for the investigation is the pregnancy trimester. The precaution about
a foetal injury when indicating an invasive exploration (imaging, endoscopy, etc.) delays the
diagnosis. The insulinomas have a rather benign potential than an aggressive nature, and their
prognosis is usually favourable, with therapeutic possibilities easy to administrate and control in
pregnant patients. Medical treatment is used in patients when there is a positive diagnosis but the
topography of the insulinoma was not identified, when the symptomatology is easy to control
through conserving therapy until the foetus is mature enough or immediately after birth, in
pregnant patients who refuse the surgical procedure, or in the case of metastasis of malignant
insulinoma. Surgical treatment indeed remains the only therapeutic method, but most often it is
scheduled usually after birth, or if the situation requires, as late as possible after the foetus has a
convenient age (after 28 weeks).
Key words: pancreatic neuroendocrine tumour (PNET), pregnancy, diagnosis and treatment
management
D. Predescu
552 www.revistachirurgia.ro Chirurgia, 114 (5), 2019
Introduction
Digestive cancers diagnosed during pregnancy
are rare and are sporadically reported. The
shift of pregnancy towards the age interval of
30-39 years old (and even 40-49 years old)
could explain the more and more frequent
superposition of pregnancy and cancer.
Various population studies (1-5) observe an
explosive increase of some digestive neo-
plasms in the last 3-4 decades, especially
when studying the 15 - 49 years old group age,
the fertile period of women. Similar to breast
cancer, digestive cancers in pregnancy are the
cancers diagnosed during pregnancy and in
the first year postpartum. Of the many
gastrointestinal sites affected by neoplasia,
the most frequent affected seem to be the
stomach, the rectum and the colon; liver and
pancreas cancers have been exceptionally
reported. The difficulty of establishing the
diagnosis of digestive cancer during pregnancy
is caused by the existence of signs and symp-
toms which can be attributed to pregnancy,
due to the common abdominal site of the
pregnant uterus and visceral neoplasm. It is
challenging to perform paraclinical tests on
these patients, an essential indicator of the
opportunity for investigation being the
pregnancy trimester. The precaution about
foetal injury when indicating an invasive
exploration (imaging, endoscopy, etc.) delays
the diagnosis.
The diagnosis and treatment protocols for
patients who are not pregnant are different
than the ones for pregnant patients; most
often, a multidisciplinary approach will define
a correct, equilibrated and optimal treatment
plan. This approach involves the association
of a medical oncologist, a gynaecologist, a
gastroenterologist, a surgeon, a paediatrician,
a neonatologist and an oncology psychologist,
together with the patient and her family.
Pancreatic Neuroendocrine Tumours
Pancreatic Neuroendocrine Tumours (PNET)
originate in the insular endocrine tissue and
are extremely rare; they have a slow, less
aggressive neoplastic development, with the
capacity of secreting and storing different
peptides and neuroamines (6). From the large
group of NET tumours, approximately 70%
have a gastroenterohepatic (GET) localisation
and represent less than 2% of the digestive
tract tumours. PNET incidence is hugely
reduced, of approximately 1/100.000 (7-9). The
association of pregnancy and PNET in the
literature (10) is exceptional; until now, only
39 cases were reported.
Mainly, from the operational point of view,
PNET are divided into two groups: 1) PNET
associated with the secretion of biologically
active substances with the emergence of
specific syndromes; 2) non-functional PNET
(NF-PNET). The distinction between these
two groups is vital for PNET diagnosis and
treatment (7-9,11).
From the group of functional PNET the
most frequent tumours are: insulinoma,
gastrinoma, VIPoma, somatostatinoma,
glucagonoma, GH-releasing factor secreting
(GRFomas), and less common PNET groups:
secreting ACHT (ACTHoma) with the
emergence of Cushing syndrome, PNET
associated with carcinoid syndrome or
hypercalcemia, or the rare ectopic PNET
secreting luteinizing hormone, renin or
erythropoietin.
NF-PNET forms are twice as frequent than
functional PNETs.
The emergence of PNET can sporadically
appear in the context of hereditary genetic
disorders, approximately 80-100% of PNET
appear in patients with MEN I, 10-17% in
patients with Hippel-Lindau syndrome and up
to 10% in patients with von Recklinghausen
disease (neurofibromatosis type 1 NF-1), all of
them being autosomal dominant transmission
diseases; MEN I is the most frequent cause,
being the consequence of a mutation in 11q13
chromosome (13,14). The patients with MEN I
develop hyperplasia of tumour growth with
various sites in endocrine and non-endocrine
tissues (parathyroid adenomas, pituitary
adenomas, carcinoid tumours, thyroid
adenomas, skin tumours, adrenal gland
tumours, etc.). As a consequence, genetic
Pancreatic Neuroendocrine Tumour in Pregnancy - Diagnosis and Treatment Management
Chirurgia, 114 (5), 2019 www.revistachirurgia.ro 553
Tumour type Hormone / Signs and symptoms Statistic incidence out
secreted peptide of functional PNET
Insulinoma Insulin Hypoglycaemia episodes 35-40%
Gastrinoma Gastrin Refractory peptic ulcer 16-30%
(Zollinger-Ellison syndrome) Diarrhoea
Glucagonoma Glucagon Diabetes <10%
Venous thromboembolism
Dermatitis & Necrolytic erythema
Diarrhoea
VIPoma Vasoactive intestinal Watery diarrhoea <10%
polypeptide (VIP) Hypokalaemia
Somatostatinoma Somatostatin Diabetes <5%
Steatorrhea
↓G
Cholelithiasis
Table 1. Signs, symptoms and incidence of functional PNET
analysis could be necessary for a complete
diagnosis (15).
The most frequent PNET in pregnant
patients is the insulinoma with the starting
point in pancreatic β-cells, with 27 out of 39
PNET worldwide reported cases until 2012
(10,16). The vast majority (!) are described in
the first trimester of pregnancy, but there
were cases at the end of pregnancy (1 case) or
immediately postpartum (4 cases). Other
PNET tumours are more rarely described,
especially in pregnant patients: gastrinoma,
VIPoma, somatostatinoma, glucagonoma, etc.
(in the order of frequency). The different
degrees of tumour aggressiveness, pregnancy
in different evolution phases, the association
of multiple MEN I specific pathologies,
inabilities to establish the diagnosis make
each case a difficult to manage entity, both
from the diagnostic and therapeutic point of
view (17-20) (
Table 1
).
The prevalence of insulinoma in general
population is of 1/250.000, the essential
characteristic being an insulin-secreting tumour
(C-peptide), with symptomatic hypoglycaemia
(the Whipple triad: low level of blood glucose,
neuroglycopenia - confusion, conscience
alteration, the enhancement of manifestations
when administrating glycemic treatment).
In our country, the largest statistics is the
one of professor I. Juvara, 55 observations
until 1984, to which are added 16 cases
published by Tr. Pătraşcu from the same
medical clinic, from 1985 to 2002 (21,22). The
same author (22) estimates that there are
under 3000 cases published worldwide, and
there are other Romanian authors who
published such cases, like for example A.
Popovici (23-25), but neither of them was
simultaneous with pregnancy. The majority of
insulinomas have a primary pancreatic site
(98%), but there are also ectopic insulinomas
in the duodenum, jejunum, ileum, lung (21).
Usually there are small tumours (5% under
0.5 cm, 34% between 0.5 - 1 cm, 53% between
1-5 cm and only 8% over 5 cm), in the head (20
– 30%) or tail (20%) of the pancreas (26). In
3,5% of cases (27), the tumours are multifocal.
Clinical Examination and Symptomatology
During a hypoglycaemic crisis, the following
symptoms may appear - memory disorders,
confusion, behavioural changes (petulance,
agitation, drowsiness), mental and physical
fatigue, sensory perception disorders (hypo-
acusis, eye accommodation disorders),
paraesthesia, amnesia. The coma is initially
superficial, but as the hypoglycaemia is
accentuated, it becomes profound, and con-
vulsions may appear (21,26,27). Attention!
Approximately 40% of the patients who
D. Predescu
554 www.revistachirurgia.ro Chirurgia, 114 (5), 2019
arrive at the hospital are in a coma or have
suffered a loss of consciousness. Establishing
a diagnosis in pregnant patients is difficult
in the first period of pregnancy because
physiologically, the glucose tends to be low.
This situation may be a consequence of the
increased secretion of insulin and sensibility
to insulin, probably as an effect of increased
oestrogen levels (28).
Furthermore, there are other signs which
could suggest the existence of a “problem”,
which are relatively common during the first
trimester of pregnancy: unexplained fatigue,
vomiting, hypotension, rare episodes of hypo-
glycaemia. The alarm raised by a prolonged or
exaggerated hyperemesis is due to the
synergistic action of acidosis, respectively of
persistent hypoglycaemia. The metabolic status
of each pregnant patient is essential; obesity
gives a certain protection against hypo-
glycaemia.
In the case of advanced pregnancies, the
rarity of the diagnosis in this stage (one single
reported case) (29) is explained by the increase
of resistance to insulin, which leads to the
absence of / minor episodes of hypoglycaemia.
In the postpartum period, once the sensibility
to insulin is restored, these tumours may be
discovered due to the appearance of specific
symptomatology.
The interesting fact in patients with insuli-
noma is that the hypoglycaemic crisis evolves
gradually, with initial sensorial and movement
disorders, then with the narrowing of conscious-
ness to coma and seizures. The clinical exami-
nation is influenced by the way glycopenia
appears and its duration: if the drop is rapid, an
adrenergic picture will emerge, if it is a slight
decrease neuropsychological signs appear. Note
that once the pregnancy period is over, the
neurological manifestations caused by
glycopenia can be considered to be psychical
postpartum disorders (!) (30).
Some patients recognise the beginning of a
glycopenic crisis, and they manage to avoid it
by ingesting carbohydrates. When evolving,
especially in case of malignancy, the crises
worsen, become more complex, subintrant.
There is no parallel between the severity of
hypoglycaemia and the severity of symptoma-
tology, the sensibility threshold being charac-
teristic to each patient (21).
Some physiological information is neces-
sary. In the first trimester of pregnancy, the
level of blood glucose is generally low due to an
increase of insulin and cellular sensibility to
insulin, as a side effect of oestrogen increase
(28). Once the pregnancy advances, a new
series of hormonal changes alter the maternal
glucose metabolism, on the one hand by
altering pancreatic β-cells function, and on the
other hand by increasing the peripheral
cellular resistance to insulin. It appears that
among the placental hormones involved, the
placental growth hormone is the most impor-
tant. It has an effect of peripheral cellular
resistance to insulin due to an overexpression
of p85α subunit, having as a consequence the
binding to IRS-1, the reduction of PI 3-kinase
activity and insulin signalling, and
the translocation of GLUT4 to the plasma
membrane (31). The same effect is due to the
presence of tumour necrosis factor (TNF -
secreted by the placenta) and circulating
leptins (32).
Another hormone involved, the placental
lactogenic hormone, stimulates the increase of
pancreatic β-cells and insulin secretion.
Paraclinical Diagnosis
The diagnosis is suggested by (117): glycaemia <
40 mg/dL concurrently with serum insulin
> 3 µU/mL, C-peptide level 200 > pmol/L,
proinsulin value > 5pmol/L, A-hydroxybutyrate
< 2.7 mmol/l, the absence of sulfonylureas in
plasma or urine and confirmed by the 72 hours
fasting plasma glucose test.
A diagnostic option would be alimentary
abstinence for 48-72 hours, under medical
surveillance, by taking regular blood samples
at 6 hours. When glucose is <60 mg/dL, blood
glucose is collected hourly. The assessment
continues until the patient begins to suffer
from hypoglycaemia (<45 mg/dL), with or
without neurological symptomatology, until
the 72 hours is accomplished. The diagnosis
becomes apparent with the sampling / the
Pancreatic Neuroendocrine Tumour in Pregnancy - Diagnosis and Treatment Management
Chirurgia, 114 (5), 2019 www.revistachirurgia.ro 555
result of plasma insulin R6 mU/mL (RIA) or
R3 mU/mL (ultrasensitive method), C peptide
R0.2 nmol/L, negative sulphonylurea and
negative insulin antibodies (33).
The suggestion of a malignancy, evident in
the presence of metastases, is brought by
severe symptomatology, associating an insulin
level and C-Peptides 2-3 times higher than in
the benign cases. A supplementary proof is the
fast positive result of the 72h fasting test
(34,35).
The standard abdominal ultrasound is not
an infallible method, having a limited
diagnostic role, especially late in pregnancy,
due to a low diagnostic sensibility; it has the
potential for identifying hepatic metastases.
Thus, the diagnosis needs to be completed with
other investigations. Generally, the insulinoma
is a small tumour < 2 cm, explaining the
difficulty of establishing a diagnosis using
imaging techniques. The endoscopic ultrasound
(EUS) is an interesting possibility, with a
redoutable diagnostic value, having a sensibility
of around 93%, a specificity of approximatively
95% and an accuracy of 93%, especially if it can
be performed in guiding histologic punctures
(the rate of unsatisfactory bioptic samples
ranges from 9 to 20%) (36-40).
The EUS diagnosis has higher rates of
success than CT or MRI but it has a series of
limitations due to pregnancy, and the risks of
this method cannot be overlooked: placental
abruption as a consequence of lumenal instil-
lation and pressure on the abdomen, diverse
foetal lesions secondary to hypotension or
maternal hypoxia during explorations which
use oversedation, teratogenesis caused by
administrated medication, etc. Here are some
mandatory rules: fasting for 6-7 hours before
the investigation, left lateral decubitus
position of the mother during endoscopy for
optimal placental perfusion, nasogastric tube,
oxygen administration to the mother and
pulse oximetry, blood pressure check, foetal
heart rate monitoring, peripheral venous line
(41,42).
Teratogenesis or abortion risks are low,
usually encountered in the first trimester. The
medication administered has to be limited to
the maximum (see endoscopy exploration in
colorectal cancer). Generally, the studies
(43-45) performed in pregnant patients who
underwent an esophagogastroduodenoscopy
(EGD) for diverse indications have not
confirmed any risks for the foetus, over 95%
having healthy newborn children and a foetal
status with no complications.
The ultrasound becomes redoutable in the
time of surgery when the identification of a
lesion is facilitated as to the simple palpation.
Intraoperative palpation, combined with
intraoperative ultrasound is over 95%
sensitive (39).
If the evolution is severe, with the
impossibility to establish a diagnosis through
other methods which could lead to a therapeu-
tic approach, radiological investigations are
performed. Imaging assessment (CT, MRI,
arteriography, radionuclide imaging) used for
identifying the tumour site/staging/ complica-
tions is most of the time-limited by the X-ray
irradiation of the foetus and by the inefficiency
of explorations, the tumours having small
dimensions, under 2 cm. In 12 cases (!) out of
the 27 reported worldwide, the diagnosis was
established only during laparotomy; the
imaging pre-operative assessments were not
efficient.
Computed Tomography (CT)
Even if essential for topography and staging,
the CT remains the subject of numerous
debates. It would be better to use other
technique every time this method can be
avoided. If the CT is crucial for establishing a
diagnosis, in his quality of the therapeutic
guide, the physician should not hesitate to use
it, since the mother’s life prevails. What can
CT bring to the evaluation of neoplasia during
pregnancy? Firstly, the method allows the
identification of the tumour and its topography
and permits a three-dimensional assessment of
the relation between the tumour and the
adjacent structures. Secondly, it will enable
assessing the histopathological nature
(malignancy/benign) and staging. CT has a
73% specificity and a 96% sensibility for
PNET diagnosis (46), the arterial phase
D. Predescu
556 www.revistachirurgia.ro Chirurgia, 114 (5), 2019
having the highest success rate in establishing
the diagnosis. The overvaluation of the T
index is the most common problem. The
dimensional limits of the method are around 1
cm. This is why tracing adenopathies/nodes
(N index) remains a problem when they are
< 1cm. Thus, the specificity in N detection is
45% (!). The essential role of CT is the assess-
ment of M index, the identification of liver
metastases have an 85% accuracy and a 97%
specificity. The data overlaps with the one
obtained through MRI (47).
Over the last 40 years, CT was contra-
indicated in pregnant patients because of the
teratogenetic and carcinogenetic effects on the
foetus. The introduction of spiral CT scan
diminished the irradiation drastically during
exploration, an entire segment (for example,
abdomen or pelvis) being scanned in 17-19
seconds for selected fields at 1.25 mm. For this
reason, the CT method was re-evaluated when
using it in pregnant patients.
The teratogenetic effect of CT radiations has
a non-cumulative (non-stochastic) nature. The
period the most susceptible to the impact of CT
radiation corresponds to the period of organo-
genesis, especially in the 2-15 weeks of
pregnancy. The teratogenetic complications
include (48,49): mental retardation, growth
disorders, microcephaly, microphthalmia,
behavioural disorders, and cataract. The thresh-
old dose (50) under which teratogenetic effects
do not appear is not known, but it seems to be of
5-15 cGy. During a spiral CT, the dose adminis-
trated to the foetus is variable (51-55),
depending on a series of elements (for example
the examination parameters). It can be of 2.9 -
4.4 cGy, the radiation dose being way under the
critical threshold, which causes congenital
malformation (56).
The carcinogenetic effect during a CT
investigation is a stochastic one, without any
threshold dose. Furthermore, there is a
connection between the moment of exposure to
radiation during pregnancy and the risk of
carcinogenesis. The smaller the pregnancy,
the higher the risk (57,58). It is considered
that at an average dose used for a CT (2-5 cGy)
the risk of cancer during childhood doubles.
Anyway, the value is low, and the recommen-
dations of the American College of
Obstetricians and Gynecologists are signifi-
cant: “very low carcinogenetic risk, abortion
not recommended” (54,55,59,60).
Another problem raised is the use of
contrast agents. There were no teratogenetic /
mutation effects in in vivo studies (61,62).
Using iodinated contrast was thought to have
a potential in developing hypothyroidism to
the foetus (63,64), but these reluctances were
eliminated through newer studies (65,66),
which have not found any side effect of the
child's thyroid function after the exposure to
these substances during the foetal period.
Magnetic resonance imaging (MRI) is the
option used in the case of pregnant patients
instead of CT. It provides information and
complex topographic relations (three dimen-
sional), with 93% sensibility and 88% speci-
ficity (46). Regarding distance staging
indices (N and M), the method has limita-
tions similar to CT, but with higher costs.
The references one has to observe are the
same as for CT. The major disadvantage is
the presence of artefacts, induced by secondary
enteral peristaltic contractions and respiratory
movements, producing image degradation
(scanning lasts 5-10 minutes) (67).
There are a series of discussions regarding
the safety of the method in pregnant patients,
because of possible teratogenetic effects of
magnetic fields and an eventual acoustic
trauma of the foetus. The in vivo studies on
animals of Heinrichs and collaborators (68)
and Tyndall (69) showed the presence of
malformations as a result to the exposure to
magnetic fields (for example eye malformations),
the death of embryos or anomalies when the
exposure took place during organogenesis (70).
As a consequence, even if similar effects were
not proven in humans, the National Radiological
Protection Board from Great Britain (71)
recommends: “it is prudent to avoid MRI in
pregnant patients in the first three months of
pregnancy”.
The possible acoustic effects induced to the
foetus by the high level of sound during MRI
are rather theoretical, without really being a
Pancreatic Neuroendocrine Tumour in Pregnancy - Diagnosis and Treatment Management
Chirurgia, 114 (5), 2019 www.revistachirurgia.ro 557
clear threat (72,73), and as to the contrast
medium, no teratogenetic effects were reported
(74,75).
Therefore, MRI will be performed in the
first trimester of pregnancy, especially for
maternal and less for foetal indications. This
method is preferable to any other investigation
method which uses ionising radiations (76).
Concerning other diagnostic methods like
nuclear techniques (for example PET-CT),
they are not usually used for evaluating
pregnant women, and there are no studies
which could prove their value, mainly due
to a weak metabolic activity of PNET to
18F-deoxyglucose. Newer studies which use
11C-5-hydroxy-tryptophan (11C-5-HTP) or
68Ga somatostatin analogues seem to be very
promising (77).
Extrapolating the use of the technique in
other tumours of the digestive tract, one can
use PET-CT for selected cases, with several
specific recommendations (reduction of
18F-FDG dose, using the 3D technology which
would allow the decrease of 18F-FDG dose,
proper hydration, mitigation of CT voltage,
etc.). PET-CT seems to be useful in identifying
the tumour site and assessing the degree of
invasion in distant sites (metastatic adenopathy,
distant metastases). The development of
technology allowed that cumulated irradiation
doses to the foetus during and after PET-CT
be at acceptable levels (1-2 cGy), comparable
to or even smaller than the doses adminis-
tered through spiral CT (78-80).
The versions using radionuclides (Osteoscan
scintigraphy - somatostatin receptor) or newer
techniques of ligands with affinity to specific
receptors can bring information about the
tumour site, but unfortunately, they can be used
only in the postpartum period because of the
harmful foetal effects.
Staging and Prognosis
Establishing a unitary PNET staging conduct,
including insulinomas, was not a useful task.
The relatively small number of cases could be
an explanation. The main competitors were
the ones of AJCC (7th edition) and ENETS
2006 Staging System Definition, a parallel
staging which was using the same TNM
(tumour–node–metastasis) terminology, but
referring to different types and spread of
PNET. Initially, AJCC staging was assimilating
TNM for exocrine cancer with the one for PNET,
while ENETS was proposing a version specific
for PNET (81,82). Therefore, TNM submitted
by ENETS had the advantage of offering an
increased layering of proposed prognosis
and treatment, as opposed to AJCC (83-88)
(
Table 2
).
Later, AJCC (8th edition) (89) lined up to
the ENETS version and introduced the same
criteria for T, N and M indices, including the G
index (histologic grade) which assesses
tumour aggressiveness and has evident
particularities specific to PNET - mitotic
index, respectively Ki67 index.
The prognosis is generally convenient,
both for the mother and foetus. Based on
impressive statistics of 432 cases, H.Y. Peiper
finds 85% benign lesions and only 15%
malignant lesions.
Malignant insulinomas are rare (5 – 15%),
and usually, in these cases, the tumours are
> 6 cm. Approximately 5% of patients already
have metastases at the moment of diagnosis,
especially liver metastases (47%) and in the
locoregional lymph nodes (approx. 30%). The
association with MEN (Multiple Endocrine
Neoplasia) is rare; only 4% of patients with
polyglandular syndromes had an insulinoma
associated. The adenomas are benign, and
they can be unique or multiple, with various
sizes (micro and macroadenomas). Macros-
copically they are well-encapsulated pinky-
reddish, yellowish or purplish round tumours,
with a consistency similar to normal pancreatic
parenchyma. Carcinomas do not have macro-
scopic characteristics which could ensure the
differentiation from a benign lesion. A tumour
size over 5 cm and the presence of metastases
are macroscopic criteria for a malignancy
diagnosis. They have more firm consistency
than benign lesions, a pinkish-grey section
with central necrosis and a tendency to invade
the adjacent pancreatic tissue.
The insulinomas have a rather benign
D. Predescu
558 www.revistachirurgia.ro Chirurgia, 114 (5), 2019
ENETS TNM AJCC TNM
TNM T1 Confined to pancreas, < 2 cm Confined to pancreas, < 2 cm
T2 Confined to pancreas, 2-4 cm Confined to pancreas, > 2 cm
T3 Confined to pancreas, > 4 cm, Peripancreatic spread, but without major vascular
or invasion of duodenal or bile duct invasion (celiac trunk, SMA)
T4 Invasion of adjacent organs or major vessels Major vascular invasion
Stage I T1 N0 M0 IA T1 N0 M0
IB T2 N0 M0
IIA T2 N0 M0 IIA T3 N0 M0
IIB T3 N0 M0 IIB T1-3 N1 M0
IIIA T4 N0 M0 III T4 AnyN M0
IIIB AnyT N1M0
IV AnyT AnyN M1 IV AnyT AnyN M1
ENETS, European Neuroendocrine Tumor Society; AJCC, American Joint Committee on Cancer; TNM, tumor, node, metastasis;
PNETs, pancreatic neuroendocrine tumors; SMA, superior mesenteric artery
Table 2. ENETS versus AJCC7TH edition staging evaluation criteria, defining PNET tumour aggressiveness through the G index
(histologic grade) in the updated AJCC (8th edition)
√G G Definition
GX Grade cannot be assessed
G1 Mitotic count (per 10 HPF)* < 2 and Ki-67 index (%)** < 3
G2 Mitotic count (per 10 HPF) = 2-20 or Ki-67 index (%)** = 3-20
G3 Mitotic count (per 10 HPF) > 20 or Ki-67 index (%)** > 20
*10 HPF = 2 mm2; at least 50 HPF (at 40x magnification must be evaluated in areas of highest mitotic density in order to adhere to WHO
2010 criteria.
**MIB1 antibody; % of 500-2,000 tumor cells in areas of highest nuclear labelling.
In cases of disparity between Ki-67 proliferative index and mitotic count, the result that indicates a higher-grade tumor should be selected
as the final grade. For example, a mitotic count of 1 per 10 HPF and a Ki-67 of 12% should be designated as a G2 NET
potential than an aggressive nature, and
their prognosis is usually favourable, with
therapeutic possibilities easy to adminis-
trate and control in pregnant patients.
Hypoglycaemia can have a possible effect
upon the vitality of the foetus, but the
increase of insulin resistance, the presence
of placental lactogenic hormone and main-
taining a reasonable glycaemia through diet
or treatment seem to minimise the impact.
The presence of malignancy leads to
remarkably different survival rates in
general population; at five years post-
operative the survival rate ranges between
16% and 56%, but in pregnant patients, only
two cancer cases were reported out of the 27
published, without information about
metastatic evolution (91).
Therapeutic Management
The treatment paradigm changes in the case
of pregnancy, because the therapeutic
management has to fulfil the interests of both
mother and foetus, without affecting one
another. The therapeutic protocols are
modified regarding both the sequence of used
methods and timing and that is why the
optimal management requires a multi-
disciplinary approach involving a medical
oncologist, a gynaecologist, a surgeon, an
anaesthesiologist, a neonatologist and some-
times surgery in mixed teams gynaecologist-
surgeon. The family should not be excluded
when decisions are made, and a series of
legal, ethical, religious, personal and emotional
factors have to be taken into account.
The therapeutic management is relatively
convenient considering the less aggressive
behaviour of the tumour: maintaining and
monitoring reasonable levels of blood glucose
through reduced meal portions frequently
administrated, glucose perfusions until the
foetus is mature enough for birth, followed by
Pancreatic Neuroendocrine Tumour in Pregnancy - Diagnosis and Treatment Management
Chirurgia, 114 (5), 2019 www.revistachirurgia.ro 559
resectional surgery (92,93).
But the situation can get more complicated
than that. The essential criteria for the thera-
peutic decision are imaging confirmation (or
not) (identifying topography), characterisation
of tumour behaviour (benign/malignant and
eventually the stage), the aggressiveness of
symptomatology, how advanced the pregnancy
is, the family's (mother’s) choice.
Medical treatment is used in patients when
there is a positive diagnosis but the topography
of the insulinoma was not identified, when the
symptomatology is easy to control through
conserving therapy until the foetus is mature
enough or immediately after birth, in
pregnant patients who refuse the surgical
procedure, or in the case of metastasis of
malignant insulinoma. When the tumour is
not identified, conserving therapy is justified,
and the surgical procedure is postponed as
much as possible. Hence it buys time for the
evolution of pregnancy, and on the other hand,
over time, the pancreatic tumour will increase,
allowing the performing of topographic
diagnosis followed by curative resection.
The hypoglycaemia crises are controlled
through a combination of dietary regimen and
intravenous administration of glucose.
Repeated meals at 2-3 hours, including at
night, with food allowing a slow-release of glu-
cose (bread, pasta, potatoes, rice); “aggressive”
concentrated sweets must be avoided. When
prodromes, which signal the onset of a hypo-
glycaemia crisis, appear the intake of sweets is
necessary, for example, fruit juice. In addition
to diet / perfusions we can take into account
the administration of beta-blockers (propra-
nolol), octreotide (controls hypoglycaemia in
over 50% of cases and controls the efficacy of
Octreoscan therapy), streptozotocin (toxic
effects on beta insular cells), Diazoxide (50 –
1500 mg/day) with an effect of hyperglycaemia
as a result of insulin issuing and glycogenolysis
stimulation. Diazoxide is the first line of
medical treatment. In the case of inefficiency,
the second line of therapy opens -
Somatostatin analogues. The B security
clearance level of FDA for the administration
of these medicinal treatments indicates a
reliable category, routinely used with other
medicines, which can be used in pregnancy
(94,95).
The presence of metastases or advanced
tumours is mostly a contraindication for resec-
tion. Chemotherapy is preferred for advanced
metastatic neoplasias; the purpose is obviously
to prolong mother’s life until a safe birth. If the
age of the foetus is convenient, chemotherapy
provides a palliative treatment option for the
pregnant patient and also in the postpartum
period. In this latter situation, the decision
for chemotherapy treatment belongs to the
mother, who has to understand the risks for
the foetus, and has to take into consideration
a series of moral, religious, ethical precepts,
etc.
The foetal exposure to chemotherapy and
its impact depends on how advanced the
pregnancy is. The consequences are more
severe at the beginning of pregnancy, due to
the alteration of rapidly dividing cells.
Congenital malformations are described in the
first trimester and development issues in the
second trimester. The immediate effects
include (96,97) spontaneous abortion, terato-
genesis, premature birth, and the late effects
may be carcinogenesis, mental retardation,
infertility, etc.
Because there is a lack of experience of
pregnant patients suffering from insulinoma,
the possible treatment plans can be decided
and equivalenced through assimilation with
data from the general population suffering
from PNET and other malignancies.
Antineoplastic drugs with molecular
weight < 500 Dalton are formally contra-
indicated, the vast majority like alkylating
agents – cyclophosphamide, antimetabolites -
methotrexate, pass through the placental
barrier. In their place, platinum salts are
recommended (Carboplatin) or antibiotics
(Doxorubicin). The usual treatment regimen
for PNET uses antimetabolites (for ex. 5-FU)
and some alkylating agents (for ex.
Streptozotocin), being the most convenient
dual formula (98), apparently with the
minimal effects on the foetus. Antibiotics or
derived Vinca alkaloids do not determine
D. Predescu
560 www.revistachirurgia.ro Chirurgia, 114 (5), 2019
foetal side effects; etoposide induces pancy-
topenia and cisplatin causes hypoacusis or
growth retardation. The therapeutic role
and side effects of new agents (oxaliplatin,
irinotecan, capecitabine) are not well explored
or documented. For example, oxaliplatin is
classified by the FDA in the toxicity category
D, with the risk of foetal lesions (99).
Foetal toxicity depending on monotherapy
versus polychemotherapy ascertains a slight
increase, from 17 to 25% in the case of
multi-drug chemotherapy (100).
Chemotherapy must not be administrated
after week 33 or 3 weeks before birth.
Molecular treatments, like targeted
therapy with mTOR pathway inhibitors (for
example Everolimus) or antiangiogenic drugs
(for instance Sunitinib or other variants), have
been used in PNETs with relatively good
results (101-104), but up to this moment, there
are not enough studies to offer information
about side effects on the foetus.
For metastatic cases, the therapeutic
possibilities are relatively modest, surgical
resection being the first treatment plan
followed by TACE (transcatheter arterial
chemoembolization), systemic chemotherapy,
intratumoral ethanol injection, radiofrequency
ablation.
Surgical treatment indeed remains the
only therapeutic method, but most often it is
scheduled usually after birth, or if the
situation requires, as late as possible after the
foetus has a convenient age (after 28 weeks).
The pregnancy requires an open surgical
intervention.
During surgery and the perioperative
period, the foetus is exposed to surgical “aggres-
sion” - laparotomy, anaesthetic and surgical
recovery, transplacental passage of drugs
(fluran, barbituric acids, diverse narcotics, etc.).
For anaesthesia, numerous guidelines present
principles and recommendations to be followed
in pregnancy, a high level of knowledge and
awareness is mandatory (105).
During surgery, the most critical problems
for the foetus are hypoxia and hypotension. An
example of problem during surgery is the
decrease of placental perfusion having a
mechanical cause, as a consequence of a
prolonged supine position, especially in
advanced pregnancies (105,106).
Post-operatively, a series of problems can
arise: infectious conditions associated or not
with fever, eating and transit disorders, risk of
thrombosis or pulmonary embolism; they can
secondary affect the foetus. Anyway, the
anxiety of the physician and family towards
surgery is most of the times higher than the
real risk itself (a rate of abortion of approxi-
mately 15%) (107).
If the diagnosis is obtained in the first half
of the pregnancy period (less than 28 weeks),
surgical ablation is necessary if the sympto-
matology is aggressive, hard to control with
conservative treatment, when the tumour is
identified or if there are solid arguments for
malignancy, the long-time until the foetus
becomes mature substantially increasing the
risk of tumour progression. In this case,
depending on the tumour stage, terminating
the pregnancy for speeding up the treatment
seems to be the desired option. Until 20-30
years ago, the risk of foetal death or abortion
was significant in the case of surgical
abdominal resections (approx. 25%).
Nowadays, because of the new surgical and
anaesthetic techniques and laparoscopic sur-
gery, the risk of foetal demise has decreased to
4%; even the abortion risk has met a drastic
decrease, the rate is double compared to the
general population (108-113). Neither the risk
of malformations is different from the general
population; however, there is a higher level of
low birth weight.
After 28 weeks, birth can safely take place
in a few weeks, followed by surgical resection
after 10-14 days. In this new context, surgery
can be performed using minimally-invasive
techniques. Once the pregnancy is over,
surgery is recommended in all cases. The topo-
graphic diagnosis of the lesion is mandatory
for a successful surgical treatment. The impossi-
bility of identifying the tumour site before
surgery asks for a rigorous examination of the
pancreas and peripancreatic area on the
operating table added to a US assessment
(114-116).
Pancreatic Neuroendocrine Tumour in Pregnancy - Diagnosis and Treatment Management
Chirurgia, 114 (5), 2019 www.revistachirurgia.ro 561
The macroscopic and ultrasound nature of
the lesion decide the surgical technique. The
presence of benignity signs opens the way for
a limited surgical intervention - enucleation,
enucleoresection - the specimen being sent for
an extemporaneous HP confirmation. The
topography of the insulinoma has a vital role
in the decision. A cephalopancreatic site
recommends an enucleoresection, whereas a
corporeo-caudal position justifies a corporeo-
caudal pancreatic resection with preservation
of the spleen. The advantage of resection is the
possibility of en-bloc resection of other tumour
sites.
The malignancy confirmation during
surgery facilitates radical interventions:
cephalic duodenopancreatectomy (DPC),
respectively corporeo-caudal splenopancrea-
tectomy (117).
The lack of tumour identification, both
before and during surgery, can justify an
eventual “blind”corporeo-caudal pancreatic
resection, but it can be considered somehow
abusive, and it is avoided through the
follow-up of the patient and the management
of hypoglycaemia crisis using drugs, and
performing periodic imaging evaluations.
The author declare no conflicts of interests.
References
1. World Health Organization. Ten statistical highlights in global
public health. World Health Statistics 2007. Geneva: World Health
Organization; 2007.
2. Ferlay J, Shin HR, Bray F, Forman D, Mathers CD, Parkin D. GLOBO-
CAN 2008, Cancer Incidence and Mortality Worldwide: IARC
CancerBase No.10. Lyon, France: International Agency for Research on
Cancer. 2010.
3. Center MM, Jemal A, Smith RA, Ward E. Worldwide variations in col-
orectal cancer. CA Cancer J Clin. 2009;59(6):366-378.
4. Center MM, Jemal A, Ward E. International trends in colorectal
cancer incidence rates. Cancer Epidemiol Biomarkers Prev. Jun
2009;18(6):1688-1694.
5. Altekruse SF, Kosary CL, Krapcho M, Neyman N, & all. SEER Cancer
Statistics Review, 1975-2007, National Cancer Institute. Bethesda,
based on November 2009 SEER data submission, posted to the SEER
web site, 2010.
6. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y,
et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic can-
cer. N Engl J Med. 2011;364(19):1817-25.
7. Massironi S, Sciola V, Peracchi M, Ciafardini C, Spampatti MP, Conte
D. Neuroendocrine tumors of the gastro-entero-pancreatic system.
World J Gastroenterol. 2008; 14(35):5377-84.
8. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors:
pancreatic endocrine tumors. Gastroenterology. 2008;135(5):
1469-92.
9. Klöppel G, Anlauf M. Epidemiology, tumour biology and histo-patho-
logical classification of neuroendocrine tumours of the tract. Best Pract
Res Clin Gastroenterol. 2005;19(4):507-17.
10. Besemer B, Müssig K. Insulinoma in pregnancy. Exp Clin Endocrinol
Diabetes. 2010;118:9-18.
11. Oberg K, Eriksson B. Endocrine tumours of the pancreas. Best Pract
Res Clin Gastroenterol. 2005;19:753-781.
12. Falconi M, Plockinger U, Kwekkeboom DJ, Manfredi R, Korner M,
Kvols L, et al. Well-differentiated pancreatic nonfunctioning tumors/
carcinoma. Neuroendocrinology. 2006;84(3):196-211.
13. O'Toole D, Salazar R, Falconi M, Kaltsas G, Couvelard A, de Herder
WW, et al. Rare functioning pancreatic endocrine tumors.
Neuroendocrinology. 2006;84(3):189-95. Epub 2007 Feb 20.
14. Jensen RT, Berna MJ, Bingham DB, Norton JA. Inherited pancreatic
endocrine tumor syndromes: advances in molecular pathogenesis,
diagnosis, management, and controversies. Cancer. 2008;113(7
Suppl):1807-43.
15. Service FJ, McMahon MM, O’Brien PC, Ballard DJ. Functioning insuli-
nomas-incidence. Recurrent and long-term survival of patients: a 60-
year study. Mayo Clin Proc. 1991;66(7):711-9.
16. Gibril F, Schumann M, Pace A, Jensen RT. Multiple endocrine
neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study
of 107 cases and comparison with 1009 cases from the
literature. Medicine (Baltimore). 2004;83(1):43-83.
17. Christiansen E, Vestergaard H. Insulinoma in a third-trimester preg-
nant woman combined with pre-eclampsia: a case report and review
of the diagnostic strategies .Gynecol Endocrinol. 2008; 24(7):417-22.
18. Dadan J, Wojskowicz P, Wojskowicz A. Neuroendocrine tumors of the
pancreas. WiadLek. 2008;61(1-3):43-7.
19. Constantinoiu S, Constantin A, Predescu D, Iosif C, Hoara P, Achim F,
et al. Somatostatinoma of the first jejunal loop in a patient with neu-
rofibromatosis Von Recklinghausen and bilateral pheochromocytoma.
Hepatogastroenterology. 2012;59(118):1874-8.
20. Norton JA, Kivlen M, Li M, Schneider D, Chuter T, Jensen RT. Morbidity
and mortality of aggressive resection in patients with advanced neu-
roendocrine tumors. Arch Surg. 2003;138(8):859-66.
21. Juvara I, Dragomirescu C. Insulinoamele în cancerul æi alte tumori ale
sistemului endocrin. Chiricuåã I. (ed). Colecåia Enciclopedia Oncologicã
(Cluj-Napoca). 1984;14:262-83.
22. Pãtraæcu Tr, Doran H, Beluæicã L, Prunaiche M, Goanåã A, Vereanu I.
Organic hypoglycemia of pancreatic cause. Chirurgia (Bucur).
2003;98(6):509-14. Romanian
23. Popovici A, Petca A, Grigoroiu M, Nica A. Insulinomas--
nesidioblastomas. Clinical experience. Chirurgia (Bucur). 1997;
92(6):387-97. Romanian
24. Ticmeanu F, Simion S, Croitoru A, Mastalier B, Angelescu M, Seicaru
T. Insulinoamele pancreatice. Chirurgia (Bucur). 2001; 96(3):227-80.
25. Târcoveanu E, Lupaæcu C, Moldovanu R, Dimofte G, Epure O, Mogoæ
V, et al. Insulinoamele pancreatice Jurnalul de Chirurgie (Iasi).
2005;1(1):42-52
26. Jensen TR, Norton AJ. Pancreatic endocrine tumors. In Sleisenger and
Fordtran’s Gastrointestinal and Liver disease, 7-th edition, Saunders
Elsevier Science. 2002. p. 988-1016.
27. Pospai D. Tumorile pancreasului endocrin. In: Tratat de hepato-gas-
troenterologie, vol. 2, Buligescu L (ed). Bucureæti: Ed. Medicalã
Amaltea; 1999. p. 971-987.
28. Rodrigues Queiróz AJ, Nazareno LS, Miranda JE, de Azevedo AE,
Teixeira da Cruz CA, Pirani Carneiro F, et al. Insulinoma diagnosed in
the postpartum: clinical and immunohistochemical features. Gynecol
Endocrinol. 2012;28(8):633-6.
29. Takacs CA, Krivak TC, Napolitano PG. Insulinoma in pregnancy: a case
report and reviewof the literature. Obstet Gynecol Surv. 2002;
57(4):229-35.
30. Müssig K, Wehrmann M, Horger M. Insulinoma and pregnancy. Fertil
Steril. 2009;91(2):656. Epub 2008 Dec 25. Comment on Insulinoma
associated with pregnancy. [Fertil Steril. 2008]
D. Predescu
562 www.revistachirurgia.ro Chirurgia, 114 (5), 2019
31. Barbour LA, Shao J, Qiao L, Pulawa LK, Jensen DR, Bartke A, et al.
Human placental growth hormone increases expression of the p85
regulatory unit of phosphatidylinositol 3-kinase and triggers severe
insulin resistance in skeletal muscle. Endocrinology. 2004;145(3):
1144-50. Epub 2003 Nov 21.
32. Kirwan JP, Hauguel-De Mouzon S, Lepercq J, Challier JC, Huston-
Presley L, Friedman JE, et al. TNF-a is a predictor of insulin
resistance in human pregnancy. Diabetes 2002;51:2207–13.
33. Service FJ. Hypoglycemic disorders. N Engl J Med. 1995;
332(17):1144-52.
34. Queiroz Almeida M, Machado MC, Correa-Giannella ML, Giannella-
Neto D, Albergaria Pereira MA. Endogenous hyperinsulinemic hypo-
glycemia: diagnostic strategies, predictive features of
malignancy and long-term survival. J Endocrinol Invest. 2006;
29(8):679-87.
35. Starke A, Saddig C, Mansfeld L, Koester R, Tschahargane C, Czygan P,
et al. Malignant metastatic insulinoma-postoperative treatment and fol-
low-up. World J Surg. 2005;29(6):789-93.
36. Anderson MA, Carpenter S, Thompson NW, Nostrant TT, Elta GH,
Scheiman JM. Endoscopic ultrasound is highly accurate and directs
management in patients with neuroendocrine tumors of the pancreas.
Am J Gastroenterol. 2000;95(9):2271-7.
37. Gouya H, Vignaux O, Augui J, Dousset B, Palazzo L, Louvel A, et al. CT,
endoscopic sonography, and a combined protocol for pre-
operative evaluation of pancreatic insulinomas. AJR Am J Roentgenol.
2003;181:987–992.
38. Ardengh JC, Rosenbaum P, Ganc AJ, Goldenberg A, Lobo EJ,
Malheiros CA, et al. Role of EUS in the preoperative localization of
insulinomas compared with spiral CT. Gastrointest Endosc.
2000;51(5):552-5.
39. Linda S. Lee Diagnosis of Pancreatic Neuroendocrine Tumors and the
Role of Endoscopic Ultrasound Gastroenterol Hepatol (N Y).
2010;6(8):520-522.
40. Klapman JB, Logrono R, Dye CE, Waxman I. Clinical impact of on-site
cytopathology interpretation on endoscopic ultrasound-guided fine
needle aspiration. Am J Gastroenterol. 2003;98:1289–1294.
41. ASGE Standard of Practice Committee, Shergill AK, Ben-Menachem T,
Chandrasekhara V, Chathadi K, Decker GA, et al. Guidelines for
endoscopy in pregnant and lactating women. Gastrointest Endosc.
2012;76(1):18-24. Erratum in Gastrointest Endosc. 2013;77(5):833.
42. Hsu JJ, Clark-Glena R, Nelson DK, Kim CH. Nasogastric enteral feed-
ing in the management of hyperemesis gravidarum. Obstet Gynecol.
1996;88(3):343-6.
43. Cappell MS, Colon VJ, Sidhom OA. A study of eight medical
centers of the safety and clinical efficacy of esophagogastro-
duodenoscopy in 83 pregnant females with follow-up of fetal in 83
pregnant females with follow-up of fetal outcome and with comparison
control groups. Am J Gastroenterol. 1996;91(2):348-54.
44. Debby A, Golan A, Sadan O, Glezerman M, Shirin H. Clinical utility of
esophagogastroduodenoscopy in the management of recurrent and
intractable vomiting in pregnancy. J Reprod Med. 2008; 53(5):347-51.
45. Frank B. Endoscopy in pregnancy. In: Karlstadt RG, Surawicz CM,
Croitoru R, editors, Gastrointestinal disorders during pregnancy.
Arlington,VA: American College of Gastroenterology, 1994: 24-29
46. Sundin A, Vullierme MP, Kaltsas G, Plöckinger U, Mallorca Consensus
Conference participants., European Neuroendocrine Tumor Society.
ENETS Consensus Guidelines for the Standards of Care in
Neuroendocrine Tumors: radiological examinations.
Neuroendocrinology. 2009;90(2):167-83.
47. Tamm EP, Kim EE, Ng CS. Imaging of neuroendocrine tumors.
Hematol Oncol Clin North Am. 2007 Jun;21(3):409-32; vii.
48. Streffer C, Shore R, Konermann G, Meadows A, Uma Devi P, Preston
Withers J, et al. Biological effects after prenatal irradiation (embryo and
fetus). A report of the International Commission on Radiological
Protection. Ann ICRP. 2003;33(1-2):5-206.
49. Wagner LK, Lester RG, Saldana LR. Exposure of the pregnant patient
to diagnostic radiations: a guide to medical management. Philadelphia;
Lippincott 1985; 19-223.
50. Berlin L. Radiation exposure and the pregnant patient. AJR Am J
Roentgenol. 1996;167(6):1377-9.
51. Damilakis J, Prassopoulos P, Perisinakis K, Faflia C, Gourtsoyiannis N.
CT of the sacroiliac joints: Dosimetry and optimal settings for a high-
resolution technique. Acta Radiol. 1997;38(5):870-5.
52. Damilakis J, Perisinakis K, Voloudaki A, Gourtsoyiannis N. Estimation
of fetal radiation dose from computed tomography scanning in late
pregnancy: depth-dose data from routine
examinations. Invest Radiol. 2000;35(9):527-33.
53. Goldberg-Stein S, Liu B, Hahn PF, Lee SI. Body CT during
pregnancy: utilization trends, examination indications, and fetal radia-
tion doses. AJR Am J Roentgenol. 2011;196(1):146-51.
54. Ratnapalan S, Bona N, Chandra K, Koran G. Physicians’ perceptions of
teratogenic risk associated with radiography and CT during early preg-
nancy. AJR Am J Roentgenol. 2004;182(5):1107-9.
55. Bentur Y. Ionizing and nonionizing radiation in pregnancy. In: Koren G,
ed. Maternal–fetal toxicology: a clinician’s guide, 3rd ed. New York, NY:
Marcel Dekker; 2001. p. 603–651.
56. Mole RH. Irradiation of the embryo and fetus. Br J Radiol. 1987;
60(709):17-31.
57. Doll R, Wakeford R. Risk of childhood cancer from fetal irradiation. Br
J Radiol. 1997;70:130-9.
58. Gilman EA, Kneale GW, Knox EG, Stewart AM. Pregnancy X-rays and
childhood cancers: effects of exposure age and radiation dose. J
Radiol Prot. 1988;8:3-8.
59. ACOG Committee on Obstetric Practice. ACOG Committee Opinion.
Number 299, September 2004. Guidelines for diagnostic imaging dur-
ing pregnancy. Obstet Gynecol. 2004;104(3):647-51.
60. Goldberg-Stein SA, Liu B, Hahn PF, Lee SI. Radiation dose
management: part 2, estimating fetal radiation risk from CT during
pregnancy. AJR, 2012; 198:W352–W356.
61. Morisetti A, Tirone P, Luzzani F, de Haen C. Toxicologic safety assess-
ment of iomeprol, a new x-ray contrast agent. Eur J Radiol 1994; 18
(Suppl 1): 21-31.
62. Ralston WH, Robbins MS, James P. Reproductive, developmental, and
genetic toxicity of ioversol. Invest Radiol 1989; 24 (Suppl 1): 16-22.
63. Rodesch F, Camus M, Ermans AM, Dodion J, Delange F. Adverse
effects of amniofetography on fetal thyroid function. Am J Obstet
Gynecol. 1976;126(6):723-6.
64. Bona G, Zaffaroni M, Defilippi C, Gallina MR, Mostert M. Effects of
iopamidol on neonatal thyroid function. Eur J Radiol. 1992; 14(1):22-
5.
65. Atwell TD, Lteif AN, Brown DL, McCann M, Townsend JE, Leroy AJ. et
al. Neonatal thyroid function after administration of IV iodinated con-
trast agent to 21 pregnant patients. AJR Am J Roentgenol.
2008;191(1):268-71.
66. Webb JA, Thomsen HS, Morcos SK; Members of Contrast Media
Safety. The use of iodinated and gadolinium contrast media during
pregnancy and lactation. Eur Radiol. 2005;15(6):1234-40. Epub 2004
Dec 18.
67. Tamm EP, Bhosale P, Lee JH, Rohren EM. State-of-the-art Imaging of
Pancreatic Neuroendocrine Tumors. Surg Oncol Clin N Am.
2016;25(2):375–400.
68. Heinrichs WL, Fong P, Flannery M, Heinrichs SC, Crooks LE, Spindle
A, et al. Midgestational exposure of pregnant balb/c mice to magnetic
resonance imaging. Mag Res Imag 1986;8:65-69.
69. Tyndall DA, Sulik KK. Effects of magnetic resonance imaging
on eye development in the C57BL/6J mouse. Teratology 1991; 43:263-
275.
70. Yip YP, Capriotti C, Talagala SL, Yip JW. Effects of MR exposure at 1.5T
on early embryonic development of the chick. JMRI 1994;4: 742-748.
71. National Radiological Protection Board. Principles for the Protection of
Patients and Volunteers During Clinical Magnetic Resonance
Diagnostic Procedures. Documents of the NRPB, Volume 2, no 1.
London: HM Stationery Office, 1991.
72. Baker PN, Johnson IR, Harvey PR, Gowland PA, Mansfield P. A three-
year follow-up of children imaged in utero with echo-planar magnetic
resonance. Am J Obstet Gynecol. 1994;170(1 Pt 1):32-3.
73. Gover P, Hykin J, Gowland P, Wright J, Johnson I, Mansfield P. An
assessment of the intrauterine sound intensity level during
Pancreatic Neuroendocrine Tumour in Pregnancy - Diagnosis and Treatment Management
Chirurgia, 114 (5), 2019 www.revistachirurgia.ro 563
obstetric echo-planar magnetic resonance imaging. Br J Radiol.
1995;68(814):1090-4.
74. Marcos HB, Semelka RC, Worawattanakul S. Normal placenta:
gadolinium-enhanced dynamic MR imaging. Radiology. 1997;205:
493-6.
75. Spencer JA, Tomlinson AJ, Weston MJ, Lloyd SN. Early report: com-
parison of breath-hold MR excretory urography, Doppler
ultrasound and isotope renography in evaluation of symptomatic
hydronephrosis in pregnancy. Clin Radiol. 2000;55:446-53.
76. Shellock FG, Kanal E. Policies, guidelines, and recommendations for
MR imaging safety and patient management. JMRI. 1991;
1:97-101.
77. Sundin A, Garske U, Orlefors H. Nuclear imaging of neuroendocrine
tumours. Best Pract Res Clin Endocrinol Metab. 2007;21:69–85.
78. Zanotti-Fregonara P, Jan S, Taieb D, Cammilleri S, Trébossen R, Hindié
E, et al. Absorbed 18F-FDG dose to the fetus during early pregnancy. J
Nucl Med. 2010;51(5):803-5.
79. Takalkar AM, Khandelwal A, Lokitz S, Lilien DL, Stabin MG. 18F-FDG
PET in pregnancy and fetal radiation dose estimates. J Nucl Med.
2011; 52(7):1035-40.
80. Hsieh TC, Wu YC, Sun SS, Chu LY, Yen KY, Kao CH. FDG PET/CT of a
late-term pregnant woman with breast cancer. Clin Nucl Med.
2012;37(5):489-91.
81. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC
cancer staging manual (7th ed). New York, NY: Springer; 2010.
82. Rindi G1, Klöppel G, Alhman H, Caplin M, Couvelard A, de Herder WW,
et al. TNM staging of foregut (neuro) endocrine tumors: a consensus
proposal including a grading system. Virchows Arch. 2006;449(4):
395-401.
83. Fischer L, Kleeff J, Esposito I, Hinz U, Zimmermann A, Friess H, et al.
Clinical outcome and long-term survival in 118 consecutive patients
with neuroendocrine tumours of the pancreas. Br J Surg.
2008;95(5):627-35.
84. Pape UF, Jann H, Müller-Nordhorn J, Bockelbrink A, Berndt U, Willich
SN, et al. Prognostic relevance of a novel TNM classification system
for upper gastroenteropancreatic neuroendocrine tumors. Cancer.
2008;113(2):256-65.
85. La Rosa S, Klersy C, Uccella S, Dainese L, Albarello L, Sonzogni A, et
al. Improved histologic and clinicopathologic criteria for
prognostic evaluation of pancreatic endocrine tumors. Hum Pathol.
2009;40(1):30-40.
86. Scarpa A, Mantovani W, Capelli P, Beghelli S, Boninsegna L, Bettini R,
et al. Pancreatic endocrine tumors: improved TNM staging and
histopathological grading permit a clinically efficient prognostic strati-
fication of patients. Mod Pathol. 2010;23(6):824-33.
87. Strosberg JR, Cheema A, Weber J, Han G, Coppola D, Kvols LK.
Prognostic validity of a novel American Joint Committee on Cancer
staging classification for pancreatic neuroendocrine tumors. J Clin
Oncol. 2011;29(22):3044-9.
88. Qadan M, Ma Y, Visser BC1, Kunz PL, Fisher GA, Norton JA, et al.
Reassessment of the current American Joint Committee on Cancer
staging system for pancreatic neuroendocrine tumors. J Am Coll Surg.
2014;218(2):188-95.
89. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK,
Gershenwald JE, Compton CC, Hess KR, et al. (Eds.). AJCC Cancer
Staging Manual (8th edition). Springer International Publishing:
American Joint Commission on Cancer; 2017.
90. Peiper H. PankretischeApudome. Chirurg 51:380, 1988
91. Lepage C, Ciccolallo L, De Angelis R, Bouvier AM, Faivre J, Gatta G;
EUROCARE working group. Europeandisparities in malignant digestive
endocrine tumourssurvival. Int J Cancer. 2010;126(12): 2928-34.
92. Whitemann VE, Homko CJ, Reece EA. Management of hypoglycemia
and diabetic ketoacidosis in pregnancy. Obst Gynecol Clin North Am.
1996;23:87–107.
93. Braga AFA, Braga FSDS, Junior JHZ, Brandão MJN, Marcondes GA,
Barbosa TDA. Insulinoma and pregnancy: anesthesia and peri-
operative management. Rev Bras Anestesiol. 2017;67(4):426-429.
94. Besemer B, Müssig K. Insulinoma in pregnancy. Exp ClinEndocrinol
Diabetes. 2010;118:9-18.7.
95. Freemark M. Ontogenesis of prolactin receptors in thehumanfetus:
roles in fetal development. Biochem Soc Trans.2001;29:38-41
96. Leslie KK, Koil C, Rayburn WF. Chemotherapeutic drugs in
pregnancy. Obstet Gynecol Clin North Am. 2005;32:627-640.
97. Beeley L. Adverse effects of drugs in the first trimester of pregnancy.
Clin ObstetGynaecol. 1986;13:177-19.
98. Delaunoit T, Ducreux M, Boige V, Dromain C, Sabourin JC, Duvillard P,
et al. The doxorubicin-streptozotocin combination for the treatment
of advanced well-differentiated pancreatic endocrine carcinoma; a
judicious option? Eur J Cancer. 2004;40(4):515-20.
99. Minter A, Malik R, Ledbetter L, Winokur TS, Hawn MT, Saif MW. Colon
cancer in pregnancy.. Cancer Control. 2005;12(3):196-202.
100. Doll DC, Ringenberg QS, Yarbro JW. Antineoplastic agents and
pregnancy. Semin Oncol 1989;16:337-346.
101. Duran I, Kortmansky J, Singh D, Hirte H, Kocha W, Goss G, et al. A
phase II clinical and pharmacodynamic study of temsirolimus
in advanced neuroendocrine carcinomas. Br J Cancer. 2006;95(9):
1148-54.
102. Pavel ME, Baudin 2, Öberg KE, Hainsworth JD, Voi M, Rouyrre N,
Peeters M, Gross DJ, Yao JC. Efficacy of everolimus plus octreotide
LAR in patients with advanced neuroendocrine tumor and carcinoid
syndrome: final overall survival from the randomized, placebo-
controlled phase 3 RADIANT-2 study. Ann Oncol. 2017;28(7):
1569-1575.
103. Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, et al. Efficacy
of RAD001 (everolimus) and octreotide LAR in advanced low- to inter-
mediate-grade neuroendocrine tumors: results of a phase II study. J
Clin Oncol. 2008;26(26):4311-8.
104. Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, et al.
Activity of sunitinib in patients with advanced neuroendocrine tumors.
J Clin Oncol. 2008;26(20):3403-10.
105. Morris MC. Obstetric anaesthesia. Philadelphia: JB Lippincott Co.
1993.
106. Leighton BL. Anaesthetic complications. In: Norris MC, ed. Obstetric
anaesthesia. Philadelphia: JB Lippincott Co; 1993. p. 616–18.
107. Doll DC, Ringenberg QS, Yarbro JW. Management of cancer during
pregnancy. Arch Intern Med. 1988;148:2058–64.
108. Saunders P, Milton PJD. Laparotomy during pregnancy: an
assessment of diagnostic accuracy and fetal wastage. BMJ. 1993;3:
165–167.
109. Skilling JS. Colorectal cancer complicating pregnancy. Obstet Gynecol
Clin North Am. 1998;25:417-421.
110. Mazze RI, Kallen B. Reproductive outcome after anesthesia and
operation during pregnancy: a registry study of 5,405 cases. Am J
Obstet Gynecol. 1989;161:1178-1185
111. Curet MJ, Allen D, Josloff RK, Pitcher DE, Curet LB, Miscall BG, et al.
Laparoscopy during pregnancy. Arch Surg. 1996;131:546-55o;
discussion 550-551.
112. Rizzo AG. Laparoscopic surgery in pregnancy: long-term follow up. J
Laparoendosc Adv Surg Tech A. 2003;13:11-15.
113. Lemaire BM, van Erp WR. Laparoscopic surgery during pregnancy.
Surg Endosc. 1997;11:15-18.
114. Iihara M, Kanbe M, Okamoto T, ItoY, Obara T: Laparoscopic
ultrasonography for resection of insulinomas. Surgery. 2001;130(6):
1086-91.
115. Tagaya N, Ishikawa K, Kubota K. Spleen-preserving laparoscopic
distal pancreatectomy with conservation of the splenic artery and vein
for a large insulinoma. Surg Endosc. 2002;16(1):217-8.
116. Wu M, Wang H, Zhang X, Gao I, Liu P, Yu B, et al. Efficacy of
laparoscopic ultrasonography in laparoscopic resection of
insulinoma. Endosc Ultrasound. 2017;6(3):149-155.
117. Kianmanesh R O'toole D, Sauvanet A, Ruszniewski P, Belghiti J.
Surgical treatment of gastric, enteric, and pancreatic endocrine
tumors. Treatment of primary endocrine tumors. J Chir ( Paris).
2005;142(3):132-49.
