Szkolenie podyplomowe/poStgraduate education
Endokrynologia Polska
DOI: 10.5603/EP.2013.0031
Tom/Volume 64; Numer/Number 6/2013
ISSN 0423–104X
Pancreatic neuroendocrine neoplasms — management
guidelines (recommended by the Polish Network
of Neuroendocrine Tumours)
Nowotwory neuroendokrynne trzustki — zasady postępowania
(rekomendowane przez Polską Sieć Guzów Neuroendokrynnych)
Beata Kos-Kudła1, Alicja Hubalewska-Dydejczyk2, Katarzyna Kuśnierz3, Paweł Lampe3, Bogdan Marek4,
Anna Nasierowska-Guttmejer5, Ewa Nowakowska-Duława6, Joanna Pilch-Kowalczyk7,
Anna Sowa-Staszczak8, Violetta Rosiek1
and other participants of the Consensus Conference (affiliations at the end of this section)
Elżbieta Andrysiak-Mamos, Tomasz Bednarczuk, Jolanta Blicharz-Dorniak, Marek Bolanowski, Andrzej Cichocki,
Jarosław B. Ćwikła, Andrzej Deptała, Wanda Foltyn, Daria Handkiewicz-Junak, Marek Hartleb, Michał Jarząb,
Arkadiusz Jeziorski, Dariusz Kajdaniuk, Grzegorz Kamiński, Aldona Kowalska, Robert Król, Leszek Królicki,
Jolanta Kunikowska, Dariusz Lange, Anna Lewczuk, Magdalena Londzin-Olesik, Przemysław Majewski,
Gabriela Mełeń-Mucha, Andrzej Nowak, Waldemar Patkowski, Marek Ruchała, Sławomir Rudzki, Philippe Ruszniewski,
Grażyna Rydzewska, Teresa Starzyńska, Katarzyna Steinhof-Radwańska, Janusz Strzelczyk, Wojciech Zajęcki,
Piotr Zdunowski, Anna Zemczak
Division of Endocrinology, Department of Pathophysiology and Endocrinology, Medical University of Silesia, Katowice, Poland
Chair and Department of Endocrinology, Jagiellonian University Collegium Medicum, Krakow, Poland
3
Department of Gastrointestinal Surgery, Medical University of Silesia, Katowice, Poland
4
Division of Pathophysiology, Department of Pathophysiology and Endocrinology, Medical University of Silesia, Katowice, Poland
5
Department of Pathomorphology, Central Clinical Hospital of the Ministry of Internal Affairs in Warsaw, Warsaw,
Jan Kochanowski University, Kielce, Poland
6
Department of Gastroenterology and Hepatology, Medical University of Silesia, Katowice, Poland
7
Department of Radiology, Medical University of Silesia, Katowice, Poland
8
Nuclear Medicine Unit, The University Hospital, Krakow, Poland
1
2
Abstract
We present revised diagnostic and therapeutic guidelines for the management of pancreatic neuroendocrine neoplasms (PNENs) proposed
by the Polish Network of Neuroendocrine Tumours.
These guidelines refer to biochemical (determination of specific and nonspecific neuroendocrine markers) and imaging diagnostics (EUS,
CT, MR, and radioisotope examination with a 68Ga or 99Tc labelled somatostatin analogue).
A histopathological diagnostic, which determines the further management of patients with PNENs, must be necessarily confirmed by
immunohistochemical tests. PNENs therapy requires collaboration between a multidisciplinary team of specialists experienced in the
management of these neoplasms. Surgery is the basic form of treatment. Medical therapy requires a multidirectional procedure, and
therefore the rules of biotherapy, peptide receptor radionuclide therapy, chemotherapy and molecular targeted therapy are discussed.
(Endokrynol Pol 2013; 64 (6): 459–479)
Key words: pancreatic neuroendocrine neoplasms; functioning; non-functioning; diagnosis; therapy; guidelines
Streszczenie
W niniejszej publikacji przedstawiono zaktualizowane zalecenia dotyczące diagnostyczno-terapeutycznego postępowania w nowotworach
neuroendokrynnych trzustki (PNEN) zaproponowane przez Polską Sieć Guzów Neuroendokrynnych.
Dotyczą one diagnostyki biochemicznej (oznaczanie specyficznych i niespecyficznych markerów neuroendokrynnych) i lokalizacyjnej
(z uwzględnieniem EUS, CT, MR, scyntygrafii receptorów somatostatynowych z użyciem analogów znakowanych 68Ga lub 99Tc).
Duże znaczenie ma rozpoznanie histopatologiczne, które determinuje dalsze postępowanie z chorymi na PNEN i musi być potwierdzone
badaniem immunohistochemicznym.
Terapia PNEN wymaga współpracy wielodyscyplinarnej grupy doświadczonych specjalistów zajmujących się nowotworami neuroendokrynnymi. Leczenie chirurgiczne jest postawową metodą postępowania. Dalsza terapia wymaga wielokierunkowego działania, dlatego omówiono
zasady bioterapii, leczenia izotopowego, chemioterapii oraz celowanego leczenia molekularnego. (Endokrynol Pol 2013; 64 (6): 459–479)
Słowa kluczowe: nowotwory neuroendokrynne trzustki; czynne hormonalnie; nieczynne hormonalnie; diagnostyka; terapia; zalecenia
Beata Kos-Kudła M.D., Ph.D., Division of Endocrinology, Department of Pathophysiology and Endocrinology, Medical University
Prof.
of Silesia, Ceglana St. 35, 40–952 Katowice, Poland, tel./fax: +48 32 358 13 66, e-mail: endoklin@sum.edu.pl
459
Pancreatic neuroendocrine neoplasms
1. Epidemiology, prognosis/survival
1.1. Pancreatic neuroendocrine neoplasms
(excluding gastrinomas)
The incidence of pancreatic neuroendocrine neoplasms
(PNENs) is approximately 0.32/100,000/year. PNENs
account for approximately 30% of all gastroentreopancreatic neoplasms (GEP NENs). 45–60% of PNENs
(in some registers up to 90%) are non-functioning.
Despite the lack of symptoms of hormonal hypersecretion, they demonstrate the ability to produce certain
substances, e.g. pancreatic polypeptide, chromogranin
A, neuron-specific enolase, β-hCG subunit, calcitonin,
neurotensin and other peptides. On the other hand,
40–55% of PNENs demonstrate excessive hormonal
activity (functioning tumours), which is reflected in
corresponding clinical symptoms [1–3].
Functioning PNENs include [1, 4]:
— insulinoma — secreting insulin,
— gastrinoma — secreting gastrin,
— glucagonoma — secreting glucagon,
— VIPoma — secreting vasoactive intestinal peptide,
— PPoma — secreting pancreatic polypeptide (often
classified as a non-functioning tumour),
— somatostatinoma — secreting somatostatin.
Very rare functioning PNENs include: CRHoma —
secreting CRH — hormone stimulating production of
corticotrophin, calcitoninoma — secreting calcitonin
and PNENs producing corticotrophin (ACTH), growthhormone-releasing hormone (GHRH), neurotensin,
parathyroid hormone-related peptide (PTHrP), rennin,
luteinising hormone (LH) and others.
The most common functioning PNENs are insulinoma
and gastrinoma [1, 4] (discussed in detail in the section
on gastroduodenal neuroendocrine neoplasms (NENs).
1.2. Clinical characteristics of PNEN
Insulinoma — insulin-secreting pancreatic neoplasm is
the most common functioning neuroendocrine tumour
of this organ. In approximately 1% of patients, an extrapancreatic location is possible (duodenum, stomach,
bile ducts, lungs) [5]. Its incidence rate is estimated at
1–3 cases/1,000,000/year. The highest incidence is observed in the fifth decade of life (between the ages of
40–45), and slightly more often in females (60%). Less
than 10% of all tumours are malignant [4]. Insulinoma is
usually single, and only 10% of patients have multiple
tumours (often in multiple endocrine neoplasia type 1
[MEN1]). In approximately 4–5% they are associated with
MEN1 syndrome [4, 5, 7, 8]. Clinical symptoms are due
to hypoglycaemia, not the presence of tumour (usually it
is no more than 2 cm in diameter). They result from neuroglycopenia: pains and vertigo, blurred vision, double
vision, abnormal behaviour, confusion, concentration
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disorders, retrograde amnesia, drowsiness, hallucinations, delusions and convulsions. In approximately 12%
of patients, loss of consciousness occurs with a grand mal
seizure. Severe hypoglycaemia may result in death. Decreased blood glucose level also causes increased secretion
of catecholic amines, and therefore: paleness, increased
perspiration, hand tremor, nausea, palpitations, hunger
(often increased body weight) and weakness. Although
the hypoglycaemic episodes usually occur several hours
after a meal, often in the morning, irregularly and with
different duration, in approximately 6% of patients hypoglycaemia can only occur soon after a meal [9]. They
may be triggered by physical effort, consumption of ethyl
alcohol or a low-calorie diet [4, 6, 7, 10–12].
A positive Whipple’s triad is helpful in diagnosing
insulinoma:
1. Clinical symptoms suggestive of hypoglycaemia;
2. Decreased blood glucose level (< 40 mg/dL;
2.2mmol/L) measured at the time of the symptoms;
3. Relief of symptoms after intake of carbohydrates.
Prognosis: in benign tumours — very good; in over
95% of such patients, a surgical procedure results in
complete recovery. In patients with distant metastases,
mean survival is less than two years. Tumour diameter
> 2 cm, Ki-67 > 2%, and various molecular and chromosomal disorders, e.g. loss of 3p or 6q, are factors
associated with decreased survival [6–8, 10–13].
Other tumours are classified as rare functioning
pancreatic neuroendocrine neoplasms (RF-PNENs). They
may occur in the pancreas and in other locations. The
clinical symptoms associated with the presence of such
neoplasms reflect the action of a hormone secreted by
the tumour. In the case of very rare neoplasms, interpretation of the symptoms is often ambiguous [4, 6].
RF-PNENs constitute < 10% of PNENs. In a large
number (40–90%) of patients with RF-PNENs, hepatic
metastases are present already at diagnosis [4, 6, 14].
VIPoma (Verner-Morrison syndrome, pancreatic cholera, WDHA syndrome): incidence rate 0.05–
0.2/1,000,000/year, malignant neoplasms in 40–70%, in
ca. 3–6% associated with MEN1; location: primarily body
of the pancreas (90%), also sympathetic nervous system,
liver, adrenal glands. Symptoms: diarrhoea (90–100%),
hypokalaemia (80–100%), dehydration (83%), acidosis,
rarely skin reddening, hypercalcaemia, glucose intolerance and functioning gall bladder disorders [4, 15–18].
Glucagonoma: incidence rate 0.01–0.1/1,000,000/
/year, malignant neoplasms 50–80%; in 1–20% associated with MEN1; location: body of the pancreas; symptoms: necrolytic erythema (67–90%), glucose intolerance
(38–87%), weight loss (66–96%), stomatitis, diarrhoea
and hypoaminoacidemia [4, 15–18].
Somatostatinoma: very low incidence rate, malignant neoplasms > 70%, in 45% associated with MEN1,
Endokrynologia Polska 2013; 64 (6)
location: pancreas (55%), duodenum/small intestine
44%, symptoms: cholelithiasis (65–90%), diabetes
(63–90%), diarrhoea (35–90%) and weight loss [4, 15–18].
GHRHoma: unknown incidence rate, malignant
neoplasms > 60%, location: pancreas (30%), lungs
(54%), small intestine (7%), other (9%), associated with
MEN1 in 16%, symptoms: acromegaly [4, 15, 16].
ACTHoma: low incidence, malignant neoplasms
> 95%, pancreatic location (4–16%), others — extrapancreatic location, rarely associated with MEN1,
symptoms: Cushing’s syndrome [4, 15, 16].
PNEN causing carcinoid syndrome: secretes
serotonin or tachykinins, very rare: pancreatic location
< 1%, malignant neoplasms 60–88%, rarely associated
with MEN1, symptoms: carcinoid syndrome [4, 15, 16].
PTHrPoma: very rarely located in the pancreas, malignant neoplasms 84%, rarely associated with MEN1,
symptoms: hypercalcaemic syndrome or, in the case of
hepatic metastases — abdominal pain [4, 15, 16].
Prognosis: in RF-PNENs, it depends on the size of
the tumour and the presence of distant metastases. The
five-year survival rate in the case of advanced disease
is estimated at 29–45%. Ki-67 > 2%, distant metastases,
chromosomal disorders and presence of cytokeratin-19
are unfavourable prognostics [4, 6, 13, 15, 16, 19].
Non-functioning pancreatic neuroendocrine
neoplasms (NF-PNENs) do not cause characteristic
symptoms of hormonal hypersecretion. In some
tumours, immunohistochemical methods have revealed the presence of various hormonal substances
produced by these neoplasms, but not secreted into
the blood circulation (or secreted in quantities which
do not result in clinical symptoms). Most of them are
well-differentiated tumours. Their incidence rate is
1.8/1,000,000/year in females and 2.6/1,000,000/year in
males. The frequency of detection increases with age,
with the peak incidence in the 6th and 7th decades
of life. In 3-53% (mean 19%), they are associated with
MEN1 syndrome (the frequency is age-related, being
higher in elderly patients) and in 13-17% with von
Hippel-Lindau (VHL) syndrom [2, 20–23].
Symptoms: NF-PNENs are usually diagnosed late,
when they are of large size, cause pressure on the
adjacent organs or invade them, or produce distant
metastases [2, 3]. The most common symptoms include:
abdominal pain (35–78%), weight loss (20–35%), loss of
appetite and vomiting (45%). Less common are internal
haemorrhages (4–20%), jaundice (17–50%) or palpable
tumours in the abdomen (7–40%) [2, 24–26]. Recent
studies by Italian researchers have demonstrated that
hepatic metastases are observed in 32% of patients
with a newly diagnosed NF-PNEN [27]. This value
is significantly lower compared to previous studies
(46–73%) [21, 28–30].
Prognosis: The mean survival of patients with
NF-PNENs in currently available studies is 38 months,
with five-year survival of 43% [2, 21]. The mean survival
of patients with distant metastases was approximately
23 months, compared to 70 and 124 months’ survival in
the case of a localised disease [2, 21, 31]. The histological
grading of the tumour is also an important factor affecting the length of survival [2, 32]. Other unfavourable
prognostic factors include: age >40 years, dynamic
development of hepatic metastases (increase of 25% of
their volume in 6-12 months), and occurrence of osseous
metastases [2, 33, 34].
2. Diagnostics
2.1. Biochemical diagnostics
Biochemical diagnostics of hormones and markers secreted by neuroendocrine neoplasms (NENs) may be
helpful in three aspects: initial diagnosis of the disease,
assessment of treatment efficacy, and prognosis.
2.1.1. Non-functioning pancreatic neuroendocrine
neoplasms (NF-PNENs)
Biochemical tests of PNENs can use chromogranin A
(CgA), which is a marker of most NENs. On the other
hand, the level of chromogranin B (CgB) may be elevated when the level of CgA is within the reference
range [2, 35, 36].
NF-PNENs often secrete pancreatic polypeptide
(PP). A simultaneous measurement of CgA and PP concentration increases the diagnostic sensitivity of PNENs
from 74% to 90%. PP is secreted in large quantities by
a significant group of NENs of the entire gastrointestinal
tract (50–80% of PNENs).
The following indicators are sometimes used in
biochemical diagnostics of non-functioning NENs:
neuron specific enolase (NSE) and the β subunit of
human chorionic gonadotropin (hCG). NSE is mainly
determined in neuroendocrine carcinoma (NEC), if
the CgA concentration is normal.
The concentration of certain peptides, mostly insulin,
gastrin and PP, increases significantly after meals; it may
remain elevated for more than six hours after a meal [4].
Therefore, blood for the assay should be collected only
after overnight fasting. For some markers, e.g. CgA, it is
not necessary to collect blood under fasted conditions.
If blood samples are not collected under fasted conditions, this fact should always be mentioned to ensure the
proper interpretation by the laboratory. Moreover, the
blood concentrations of all NEN markers, except insulin,
are elevated in patients with renal failure, so it is difficult
to interpret results in such patients. Among numerous
markers assessed in the blood, CgA is a prognostic factor
for most NENs [37, 38, 39].
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Pancreatic neuroendocrine neoplasms
2.1.2. Functioning pancreatic neuroendocrine neoplasms (F-PNENs)
Biochemical diagnostics of all F-PNENs requires the
evidence of increased serum concentrations of specific
hormonal markers (e.g. gastrin in Zollinger-Ellison syndrome (ZES) or insulin in insulinoma) in combination
with clinical symptoms/Laboratory changes indicating
the hypersecretion of an appropriate hormone, such as
excessive secretion of gastric juice in ZES, hypoglycaemia in insulinoma, etc. [4]. In a great number of sporadic
NENs, the type of cells may change and tumours may
produce various additional peptides (apart from those
specific for the tumour). It is related to worsening of
the prognosis, especially when the tumour additionally
secretes ACTH [40, 41].
Most insulinomas are ‘benign’ tumours with proper
serum CgA levels which increase with metastases.
Insulinoma
The diagnosis of insulinoma is based on the following
criteria:
— documented glycaemia ≤ 2.2 mmol/L (≤ 40 mg/
/dL) and concomitant inadequate concentration of
insulin ≥ 6 mU/L (≥ 36 pmol/L);
— C-peptide level ≥ 200 pmol/L;
— proinsulin level ≥ 5 pmol/L.
Interpretation of the above criteria should include
drug-induced hypoglycaemia by verifying the serum and/
or urinary levels of sulphonylurea and its metabolites [4].
When diagnosing insulinoma, the 72-hour fasting
test is still the gold standard, although some studies
report that a 48-hour test may be sufficient. The fasting
test is performed in inpatient conditions, with serial
measurements of the blood glucose level. Patients with
insulinoma usually develop hypoglycaemia within
24 hours. Increased levels of ketones in urine indicate
the proper fasting test in healthy people. In 5% of
patients, hypoglycaemia may occur after meals [42].
When the symptoms of hypoglycaemia occur and the
glucose level in the blood is ≤ 2.2 mmol/L (≤ 40 mg/dL),
the blood should be collected for C-peptide, proinsulin
and insulin assays. The lack of adequate suppression of
insulin in hypoglycaemia confirms the presence of an
independently secreting insulinoma-type tumour [4].
In one of the recent studies, the most sensitive criterion for diagnosing insulinoma was the coexistence
of elevated proinsulin levels and fasting glycaemia of
≤ 2.5 mmol/L (≤ 45 mg/dL) [4].
Gastrinoma
The biochemical diagnostics of gastrinoma are discussed
in the section on gastroduodenal NENs (pp. 444–458).
* evidence level according to CEBM [152]
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Beata Kos-Kudła et al.
2.1.3. Rare functioning pancreatic neuroendocrine
neoplasms (RF-PNENs)
Biochemical diagnostics of a RF-PNEN includes confirmation of increased serum concentrations of specific
biochemical markers, e.g. glucagon is suspected glucagonoma (positive result > 1,000 pg/mL), vasoactive
intestinal peptide (positive result > 170 pg/mL), somatostatin (positive result in pancreatic neoplasms location
is over 50 times higher than the reference values) [34].
CgA, which is a general marker, can only be used
to confirm the presence of a neuroendocrine neoplasm
and monitor the course of the disease, but it cannot constitute the basis for the diagnosis of functioning PNENs.
All biochemical tests should be performed during
the first visit. Suspected Cushing’s syndrome due to
PNEN should be confirmed by 24-hour urine or midnight serum cortisol measurements, or by determination of cortisol concentration in saliva. If necessary, the
determination of cortisol with the use of the dexamethasone suppression test should be performed.
The assessment of markers specific for NEN is useful
in the diagnosis and monitoring of various neoplasms
[43], as set out in Table I. Indications for their determination depend on the clinical presentation of the patient
with a PNEN.
2.1.4. Pancreatic neuroendocrine carcinoma (PNEC)
An assessment of the CgA levels and other hormonal
markers in this group of PNEC usually produces negative results. NSE may be used as a marker for these
neoplasms [34].
Minimal consensus on biochemical tests:
Determination of plasma CgA level should be the basic
biochemical test in patients with suspected PNENs [44]. In
non-functioning NENs, pancreatic polypeptide (PP) can
be used for early detection of PNENs in MEN1 and PNEC
(especially with low CgA level).
Determination of specific markers (gastrin, insulin,
serotonin, VIP, glucagon, etc.) should be performed if the
patient presents symptoms suggestive of a hormonal clinical
syndrome. Specific dynamic tests are very rarely performed.
(*evidence level 3).
2.2. Pathomorphological diagnostics
2.2.1. Pathogenesis
The term ‘pancreatic neuroendocrine neoplasms’ refers
to tumours arising from a pluripotent stem cell of the
pancreatic ducts with neuroendocrine differentiation.
The term ‘islet cell tumour ’, frequently used in the
Endokrynologia Polska 2013; 64 (6)
Table I. Specific markers for various PNENs (modified according to [34, 43])
Tabela I. Specyficzne markery dla różnych PNEN (zmodyfikowane wg [34, 43])
Tumour type
Laboratory tests
Expected results
All pancreatic NENs
CgA
Increased concentration only in metastatic tumours
Non-functioning NENs
PP, NSE, hCG
Increased concentration
Insulinoma
CgA, insulin, glucose,
Inadequate increase in the insulin/glucose concentration ratio
C-peptide or proinsulin
Increased concentration
Gastrinoma
Gastrin
Increased concentration
Glucagonoma
Glucagon, enteroglucagon
Increased concentration
VIPoma
VIP
Increased concentration
Somatostatinoma
SST
Increased concentration
PPoma
PP
Increased concentration
MEN1
CgA, gastrin, calcium, PTH, insulin,
glucagon, PP, PRL
Increased concentration of selected markers
CgA — chromogranin A; CgB — chromogranin B; hCG — human chorionic gonadotropin; 5-HIAA — 5-hydroxyindoleacetic acid; NSE — neuron specific enolase;
PP — pancreatic polypeptide; PTH — parathyroid hormone; SST — somatostatin; VIPoma — tumour secreting vasoactive intestinal peptide; PRL — prolactin
Table II. ENETS and TNM UICC/AJCC classification, 2011
Tabela II. Klasyfikacja TNM ENETS i AJCC/UICC, 2011
Feature T according to TNM TNM ENETS
TNM AJCC/UICC, 2011
T1
Tumour limited to the pancreas, < 2 cm in diameter
Tumour limited to the pancreas, < 2 cm in diameter
T2
Tumour limited to the pancreas, 2–4 cm in diameter
Tumour limited to the pancreas, > 2 cm in diameter
T3
Tumour limited to the pancreas, > 4 cm in diameter or
invading duodenum or bile tract
Tumour invading the adjacent tissues, without invasion
of the main vascular trunks (coeliac axis, superior
mesenteric artery)
T4
Invasion of the adjacent organs or the wall of large vessels Invasion of the wall of large vessels
past, is incorrect due to NEN histogenesis, as these
neoplasms do not arise from pancreatic islets. Pathomorphological diagnostics of NENs is based on the
standardised WHO classification. The diagnosis is confirmed by immunohistochemical methods, in order to
assess the expression of neuroendocrine markers: chromogranin A and synaptophysin, and the Ki-67/MIB1
proliferation index. Immunohistochemical examination
of the hormonal substances produced by pancreatic
cells is not sufficient for the diagnosis of functioning
or non-functioning tumours [34]. Pancreatic cells may
demonstrate immunohistochemical expression of the
analysed products even in minimal quantities, without
any clinical significance.
2.2.2. Diagnostic algorithm
Histopathological diagnostics of PNENs requires an
assessment of [45–50]:
— histological type according to the WHO 2010 classification;
— histological grade according to the ENETS/WHO
2010 classification;
— pTNM stage of clinical and pathological advancement
(according to ENETS, AJCC/UICC of 2010) (Table II);
— each diagnosis of NEN must be confirmed by immunohistochemical examinations with the use of
antibodies against chromogranin A and synaptophysin, and by the Ki-67/MIB1 proliferative activity
assessment;
— in certain cases, products secreted by NENs, such
as gastrin, insulin or glucagon may be assessed.
These markers are more useful for detection of the
metastases of functioning tumours, especially if the
original site is unknown. Clinical staging of NENs
is presented in Table III.
Classification of NENs according to WHO 2010
and the histological grade of NETs according to the
standardised ENETS/WHO 2010 system are presented
in the section on general recommendations for the
management of GEP NENs (pp. 418–443).
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Pancreatic neuroendocrine neoplasms
Table III. Clinical staging of PNENs
Tabela III. Stopień klinicznego zaawansowania PNEN
Clinical stage
Comments
Stage IA
T1 N0 M0
Stage IB
T2 N0 M0
Stage IIA
T3 N0 M0
Stage IIB
T1-3 N1 M0
Stage III
T4, any N M0
Stage IV
Any T, any N M1
2.2.3. Prognostic factors in the histopathological report
In the histopathological examination, it should be noted
that nodules smaller than 5 mm are referred to as microadenoma, and are not considered in the histopathological report. Multiple foci are characteristic for PNENs,
especially in MEN1, in over 30% of gastrinoma cases
and 13% of insulinoma cases. Therefore, a very careful
microscopic assessment of the surgical material, involving cross-sections of the pancreatic parenchyma at 3 to
5 mm intervals, is necessary. In each case, an assessment
of resectability is an important prognostic parameter.
In order to perform it, it is necessary to evaluate macroscopically and microscopically the surgical margins:
transpancreatic, retroperitoneal and radial, created by
the posterior wall of the surgical material. Assessment of
the vascular and neural invasion is also recommended,
as according to certain clinical studies it is associated
with lymph nodes metastases and shorter life expectancy. Coagulative necrosis, local or geographic, is
another prognostic factor, as it correlates with a high
grade of histological malignancy of the tumour.
The morphological picture of the tumour, comprising tumour tissue architecture and characteristics
of its cells, is also reflected in the tumour differentiation stage [51, 52]. Under a light microscope,
PNEN usually corresponds to a well-differentiated
neuroendocrine neoplasms G1 or well-differentiated
neuroendocrine neoplasms G2. Organoid structures
in the form of solid nests, trabecular or labyrinthine
systems, or structures resembling glands and rosettes,
are characteristic. They are accompanied by a varying quantity of tumour stroma and numerous blood
vessels surrounding the tumour nests. It is worth
emphasising that amyloid deposits are typical for
a functioning tumour such as insulinoma, whereas
glandular-like structures and psammomatous bodies
are characteristic of somatostatinoma. The characteristics of neuroendocrine neoplasm cells are well
* evidence level according to CEBM [152]
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Beata Kos-Kudła et al.
known to differ from other neoplasms. They are small
or medium-sized, with acidophilic or amphophilic
and granular cytoplasm. The nuclei are round or
oval, usually situated centrally in the cell. A typical
feature of a NEN, which helps to distinguish it from
adenocarcinoma, is fine-grained chromatin, referred
to as ‘salt and pepper ’. Apart from the above typical features of neuroendocrine tumours, their cells
may present a different picture, creating oncocytic,
clear cell, fat-rich and rhabdo-like variants. PNENs
may then resemble melanoma, clear cell renal cell
carcinoma or adrenal cortical carcinomas. Diagnostic
errors are caused by incorrect differentiation between
a PNEN and a pancreatic ductal adenocarcinoma
or acinocellular carcinoma, or clear cell carcinoma
metastases from other organs.
To sum up, pathomorphological diagnostics of
pancreatic NENs requires experience on the part of
the pathomorphologist, co-operation of an interdisciplinary team of specialists, and access to an immunohistochemical laboratory.
Minimal consensus on pathology
Minimal histopathological report for a PNEN should include:
— histological type of the neoplasm, considering the division into well-differentiated neuroendocrine neoplasms
(NEN), neuroendocrine carcinomas (NEC) and mixed
neoplasms (MANEC);
— histological G grading referring to well-differentiated
neoplasms (NEN G1, NEN G2);
— pTNM staging according to ENET and AJCC/UICC
classifications (it is important to provide affiliation of the
classification in each case);
— assessment of surgical margins.
Histopathological diagnosis of NEN must be necessarily
confirmed by immunohistochemical tests assessing expression of the neuroendocrine markers: synaptophysin and
chromogranin A, as well as the Ki-67 proliferative activity
using the MIB1 antigen [53] (*evidence level 3).
2.3. Imaging diagnostics
2.3.1. Endoscopic diagnostics
Classical gastrointestinal endoscopy is practically of no
importance for the diagnostics of PNENs.
2.3.2. Ultrasonography
Transabdominal ultrasonography
The sensitivity of conventional ultrasonography (USG),
mostly performed as the first-line examination in the
detection of primary tumours, and in assessment of
the staging of the disease, is low for small tumours. On
Endokrynologia Polska 2013; 64 (6)
average, ultrasonography detects approximately 30%
of primary insulinomas and gastrinomas. The sensitivity of this method increases for detection of hepatic
metastases, when it amounts to 50–80%. For larger
tumours, mostly non-secreting pancreatic tumours
and late-diagnosed glucagonoma, the sensitivity of
transabdominal USG is higher [54, 55, 56].
2.3.3. Endoscopic ultrasonography
Endoscopic ultrasonography (EUS) enables precise imaging of the pancreas, and it is the most sensitive of the
methods presently used in the diagnostics of pancreatic
focal lesions (it detects lesions of 1–2 mm in diameter);
normal results of EUS practically exclude the presence of
a pancreatic tumour [57]. EUS imaging is useful when the
CT scan image is inconclusive. Biopsy is recommended to
confirm the neoplastic character of the lesion [58].
EUS enables the ability to:
— localise functioning neoplasms (diagnosed on the
basis of clinical and/or biochemical symptoms);
— obtain the material for histopathological examination;
— tattoo small focal lesions before the planned surgical treatment;
— perform diagnostic imaging of non-functioning
PNENs;
— conduct screening tests in patients with MEN1.
In the case of small insulin-secreting tumours, the
EUS sensitivity is up to 94% [59–64]. Tumour location in
the tail of the pancreas or the presence of small, slightly
hypoechogenic nodules located deep into the pancreatic
parenchyma and multifocal nodules can be a limitation
for EUS [59, 65]. According to the literature, in the case
of tumours in the pancreatic tail, the sensitivity of the
examination can decrease to 60%. Diagnostic sensitivity
of the examination in pancreatic gastrinoma tumours is
nearly 100%, but it decreases in the case of multifocal lesions and those with an extra-pancreatic location; in the
case of gastrin tumours located in the duodenum and
outside the pancreatic parenchyma, the sensitivity of the
test is estimated to be approximately 50% [63, 66].
EUS is also important in the differential diagnostics
of PNENs of ambiguous character, and in pre-operative
assessment of the neoplasm stage. There are certain
specific ultrasonographic characteristics which allow
differentiation between pancreatic carcinomas and
neoplasms of the neuroendocrine origin, as well as between functioning and non-functioning neoplasms [67].
The usefulness of EUS for the assessment of the stage
of lesions has also been confirmed, particularly for the
evaluation of vascular invasion [68].
EUS is also used to perform fine-needle biopsy
through the stomach wall. It is believed that this route
of access, compared to percutaneous biopsy, reduces
the danger of the spreading of neoplastic cells. In the
study by Voss et al. [69], the diagnostic accuracy of
such biopsy for pancreatic carcinoma was 81%, and for
PNEN was 46.7%.
Presently, third generation contrast agents are
entering ultrasound imaging. These agents are composed of gas microbubbles in a phospholipid shell,
characterised by a long half-life in the bloodstream and
enhanced, perfusion-dependent greyscale. Currently,
studies are conducted on the use of contrast enhanced
ultrasound (CEUS) for the differential diagnostics of
pancreatic tumours, including PNENs [70]. CEUS
detects tumours smaller than 2 cm in diameter with a
sensitivity comparable to EUS (95%). With respect to
PNENs, the method’s sensitivity is up to 94%, specificity reaches 96%, the positive predictive value — 75%,
and the negative predictive value is up to 99%. The
image of neuroendocrine neoplasms has a characteristic echo pattern after intravenous administration of
the contrast agent: in the arterial phase, echogenicity
increases intensively and quickly decreases as the
contrast agent washes out in the venous phase [2].
The highest accuracy in the differential diagnosis of
pancreatic neoplasms and in detection of small (less
than 1 cm) lesions is achieved by combining the EUS
technique with intravenous administration of the
contrast agent (Contrast-Enhanced Harmonic Endoscopic
Ultrasonography, CH-EUS) [71].
In pre-operative diagnostics, it is possible to inject
ink into the tumour tissue during EUS, which enables
faster intraoperative location of the lesion. Using this
method is important, especially in the case of laparoscopic procedures, during which it is impossible to
palpate the pancreatic lesions. Apart from that, precise
location of the lesion enables the ability to achieve an
adequate resection margin and to preserve healthy
pancreatic tissue. However, it is worth emphasising that
tattooing may cause acute pancreatitis [72, 73].
A special indication for conducting EUS examination is MEN1. The incidence of pancreatic lesions in
this group of patients is estimated as 40–80%. Although
functioning neoplasms can be early diagnosed due
to typical clinical and biochemical symptoms, nonfunctioning neoplasms (ca. 50% of lesions) in most
patients are diagnosed late, which determines a poor
prognosis. EUS is recommended as the most sensitive
and economically justified method of monitoring these
patients, as early detection of a pancreatic lesion enables
the implementation of radical treatment.
2.3.4. Intraductal ultrasonography
Intraductal ultrasonography (IDUS) may surpass EUS
in the detection of PNENs. In this method, a probe of
465
Pancreatic neuroendocrine neoplasms
2 cm in diameter is introduced into the duct of Wirsung
through the duodenoscope channel.
2.3.5. Intraoperative ultrasonography
The sensitivity of intraoperative ultrasound (IOUS) in
the detection of small PNENs is similar to that of EUS.
The sensitivity of this examination, combined with
intraoperative palpation assessment, is up to 97%. In
the case of gastrinoma, the sensitivity of the test within
the pancreas is close to 100%, but decreases to 58% with
extra-pancreatic location. IOUS also allows detection of
multifocal tumours and metastases in the liver. IOUS
examination is also performed during laparoscopy [74].
2.3.6. Computed tomography (CT) and magnetic
resonance imaging (MR)
Presently, according to current guidelines, a spiral
multidetector CT (MDCT) and MR imaging are used for
the diagnosis of parenchymal abdominal organs. These
methods are especially important in the assessment of
the stage of the neoplastic disease, and in monitoring
of the response to treatment [75]. They are also useful
for the assessment of anatomical location and resectability of the primary lesion. Computed tomography
enables performing a targeted biopsy from the lesion.
The sensitivity of each imaging method depends on the
location and type of tumour [64, 76].
Prior to administration of the contrast agent, functioning PNENs are usually isodense, rarely hypodense
compared to the remaining pancreatic parenchyma,
and calcifications are clearly visible. Most tumours are
richly vascularised (insulinoma 80%), so in the arterial phase, MDCT is intensively enhanced. Metastases
demonstrate a similar behaviour. Therefore, the MDCT
examination should cover both pancreas and liver in
the arterial phase. In this phase of the test, it is also
possible to assess the tumour/coeliac arteries relation.
In the parenchymal phase, the assessment is limited to
the pancreas, and it concerns tumour morphology and
the level of contrast washing out. The portal venous
phase again comprises the pancreas, liver and hepatic
portal system [77].
Some researchers have suggested conducting the
examination also in the delayed phase (150 seconds
after the administration of the contrast agent), and in
order to further assess the level of washing out of the
contrast material from the tumour. In typical neuroendocrine neoplasm, the contrast enhancement should
decrease in the delayed phase relative to the arterial
phase by at least 60 HU. Other types of enhancement
in PNEN include uneven washout of the contrast agent
(from more than half or from less than half of the tumour mass), or slowly increasing enhancement when
the tumour is better visible in the equilibrium phase,
466
Beata Kos-Kudła et al.
in which the uptake in the normal pancreatic parenchyma decreases. This is a behaviour characteristic for
tumours with a high connective tissue content. In the
parenchymal and secretive phase, neuroendocrine
neoplasms are not always isodense and are therefore
invisible in the CT scan. Certain neoplasms in these
phases of examination maintain the enhancement or
only begin the process of collecting the contrast agent.
Slightly enhanced neoplasms are usually poorly differentiated, so the level of enhancement correlates with
the length of patient survival [78, 79]. Non-functioning
neoplasm demonstrate a lower enhancement after
the administration of the contrast agent, and are heterogeneous due to the necrotic areas. Calcifications in
adenocarcinomas are very rare, whereas in functioning
and non-functioning PNENs they are found in at least
25% of cases. In larger tumours, the pancreatic duct
is dilated, and parenchymal atrophy is observed. The
only features that distinguish malignant lesions from
benign ones are invasion of the adjacent structures and
distant metastases. Hepatic metastases are detected in
the arterial phase of the examination [76].
Due to shortened time of scanning, a reduced
number of movement artifacts, and obtaining thin (1–2
mm) tissue layers, MDCT enables multi-dimensional
and spatial reconstructions, which facilitates imaging
of structures smaller than 1 cm, and allows a complete
assessment of the vascular invasion of the tumour [80].
The sensitivity of contrast-enhanced MDCT using 1 mm
layers in diagnosis of insulinoma reaches 85–94% [81,
82], whereas for various types of NENs the sensitivity
of multidetector CT is 50–90%, and the specificity is
96% [2, 83, 84].
The role of CT scans in the assessment of PNEN consists in the description of tumour morphology with precise location, and, with reference to organ-transgressing
infiltration, in determination of the adjacent fat tissue
invasion, infiltration of the duodenum, common bile
duct, stomach, spleen, intestinal loops, adrenal glands,
as well as determination of arterial and venous invasion, providing information about the invaded part and
length of the vessel. The description should also contain information concerning enlarged regional lymph
nodes and the assessment of the liver for metastases.
Assessment according to TNM classification should be
possible on the basis of CT description [1].
MR conducted according to the optimal protocol
has a similar sensitivity in the diagnosis of PNEN as CT,
which is up to 80–90%. MR offers a higher tissue resolution in combination with multi-dimensional imaging.
Limitations of this method include: reduced availability
(compared to CT scanning), higher price, longer duration of examination and the necessity of co-operation
with the patient. The method is recommended espe-
Endokrynologia Polska 2013; 64 (6)
cially for younger patients, as it does not require the use
of ionising radiation, and also in patients whose CT scan
image is inconclusive. Neuroendocrine neoplasms are
hypointense on T1-weighted images, and hyperintese
on T2-weighted images. Intravenous administration of
the contrast agent increases sensitivity of the method
[77]. In a multi-phase examination following the intravenous administration of the contrast agent, the images
are enhanced according to the CT enhancement pattern provided above. In addition, in MR spectroscopy,
which uses the chemical shift displacement, it is possible to determine the chemical composition of tissues.
A relatively increased lipid content in NENs facilitates
differentiation in uncertain cases.
In recent years, a diffusion weighted imaging
(DWI) method has also been used, in which the level
of water diffusion limitation in the tissue is assessed.
Neuroendocrine neoplasms, particularly those with
a high connective tissue content, cause limitation of
the diffusion of water molecules, which generates an
intensive signal in the DWI sequence, accompanied by
lowered ADC. DWI is particularly valuable in tumours
with a significant connective tissue component, which
are poorly or atypically enhanced after intravenous
administration of the contrast agent [54, 85].
2.4. Radioisotope diagnostics
The recently observed development of diagnostic methods with the use of labelled somatostatin analogues in
examinations using the technique of single proton emission computed tomography (SPECT/CT) and positron
emission tomography (PET/CT), also in combination
with intraoperative detection with the use of isotope
probe, contributes to higher detection rates of PNENs
and their metastases. These tests can identify lesions
undetected by anatomical imaging methods, increasing
the chances of locating the primary focus and determining the actual stage of the neoplasm [76, 86]. They may
also be the first-line method in the diagnostics of early
recurrence, in monitoring the disease and in choosing
the optimal treatment. A positive result of receptor
scintigraphy is also the basis for introducing therapy
with ‘cold’ and/or ‘hot’ (bound to a radioactive isotope)
somatostatin analogues (SSA) [87, 88].
111
In-Octreoscan, used until recently in scintigraphic
diagnostics, has been substituted in Poland with 99TcEDDA/HYNIC-Tyr(3)-octreotide. The sensitivity of
somatostatin receptor scintigraphy (SRS) for tests with
the use of 111In-Octreoscan in the diagnosis of the primary lesion for various PNENs has been estimated at
70–100% for gastrinoma, VIPoma and glucagonoma
[89], at 50–60% for insulinoma [86], and at ca. 90%
for non-functioning tumours. Scintigraphy with the
use of 111In-Octreoscan enables the ability to detect
approximately 90% of GEP NENs hepatic metastases
[90]. Generally, the sensitivity of SRS is estimated to be
71–96% [91], whereas the specificity ranges between
76% and 95% [89, 91]. Using the SPECT technique significantly improves the sensitivity of the method [89].
The usefulness of increasingly popular somatostatin
analogues labelled with technet 99m for the diagnostics
of PNENs has been confirmed by many authors [87, 92].
99mTc-EDDA/HYNIC-Tyr(3)-octreotide (99mTc-EDDA/
HYNIC-TOC) 99mTc-[99mTc-EDDA/HYNIC]octreotate
demonstrates a higher uptake by the pancreatic and pituitary tumour cells having somatostatin receptors than
octreotide. The possibility of combining scintigraphic
and tomographic images with the use of fusion image
SPECT/CT enables a precise detection of the anatomical location of the lesion visible in molecular imaging,
and contributes to increased diagnostic sensitivity and
specificity [93].
Presently, the most sensitive examination in the
diagnostics of well-differentiated NENs is definitely
the PET/CT test with the use of somatostatin analogues
(SSA) labelled with 68Ga: DOTA-TOC, DOTA-TATE
and DOTA-NOC, and in the future probably also with
64
Cu-TETA-octreotide [94]. In the diagnostics of PNENs,
it is also possible to use the PET/CT test with the use
of 18F-FDOPA. The usefulness of 18F-FDOPA has been
evaluated in different types of NENs and at different
stages of the neoplastic process. Becherer et al. demonstrated a higher diagnostic sensitivity of 18F-FDOPA
PET compared to SRS and CT scanning in patients with
advanced NENs, both with regard to staging and in
the diagnostics of osseous metastases. However, SRS
proved superior in planning treatment with SSA [95].
The examination with 18F-FDOPA enables the exclusion of artifacts related to physiological activity in the
peripancreatic tissues [44]. Other studies comparing
68
Ga with 18F-FDOPA have indicated the indisputable
superiority of the 68Ga-DOTA-TATE test in the detection and staging assessment of NENs, whereas PET/
/CT examination with 18F-FDOPA should be performed
when the test with gallium is negative [96]. In the case
of insulinoma, the diagnostic value of 18F-FDOPA is
disputable [97]. Another tracer used in diagnostics of
PNENs is 11C-5-hydroxytryptophan (5-HTP) [2]. It is
not used in Poland. 18F-Fluorodeoxyglucose (FDG) is
used in the diagnostics of fast-growing and aggressive
PNENs and PNECs with a poor prognosis.
The next step to improve sensitivity of location diagnostics of small PNETs (gastrinoma, insulinoma) is using
an intraoperative radioisotope probe (RGS) [98, 99].
In recent years, new diagnostic tracers for PNENs
have been introduced. They enable the location of
certain types of functioning tumours, and due to diagnostic effectiveness in the future they may become
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Pancreatic neuroendocrine neoplasms
important imaging tools for PNENs. One of them is
a labelled analogue of glucagon-like peptide-1 (GLP-1).
Due to a very high expression of receptors for GLP-1 in
some neoplasms (in 100% of benign insulin-secreting
tumours), scintigraphy with the use of labelled GLP-1
analogues may become a diagnostic method competing
with SRS [100]. Several reports concerning imaging of
insulinoma on animal models and in humans have been
published. A high tracer uptake by this tumour was
demonstrated (high tumour/background ratio), and the
quality of the received image was assessed as very good.
Using a GLP-1 analogue labelled with 111In, insulinoma
implanted in a mouse was completely destroyed. In
the study, the GLP-1 analogues labelled with 111In (e.g.
[Lys40(Ahx-DOTA-111In)NH2]-Exendin-4), 99mTc
([Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4)
and 68Ga were used. Preliminary study results indicate a lack of receptor expression for GLP-1 in most
malignant forms of insulinoma (positive SRS is more
common in these cases), which suggests the usefulness
of imaging with labelled GLP-1 analogues for the differentiation of benign and malignant insulin-secreting
tumour forms [101, 102].
2.5. Location diagnostics of different PNENs
2.5.1. Insulinoma
Most frequently they are small tumours, less than 2 cm
in diameter (60–70% of cases), usually classified as group
1 according to the WHO classification; they are mostly
single (85%) and located in 99% of cases in the pancreas,
with a similar prevalence for all parts of the organ [10].
While conducting location diagnostics in the search for
the cause of hypoglycaemia with hyperinsulinism, it
should be noted that in approximately 4% of cases, the
reason is hyperplasia of β cells (nesidioblastosis; NIPHS,
noninsulinoma pancreatogenous hypoglycaemia). In
the case of insulinoma, the most sensitive imaging examinations include endoscopic ultrasonography (EUS)
and intraoperative USG. The usefulness of classical
USG, EUS, IOUS, CT and MRI is discussed in detail
in the section concerning the imaging diagnostics of
PNENs.
Another test used in the diagnostics of insulinoma is
SRS. It is important to note that only 50-60% of insulinoma tumours demonstrate somatostatin receptor expression (according to the literature data, the frequencies of
expression for different SSTR types in insulinoma are as
follows: SSTR1 — 51%, SSTR2 — 69%, SSTR3 — 62%,
SSTR4 — 39%, and SSTR5 — 66%) [86]. If the results of
other imaging tests are negative, a PET/CT scan with
68
Ga-somatostatin analogue may be performed [4].
Transhepatic portal venous insulin sampling (THPVS)
and angiography with a selective calcium stimulation
test [103] are very rarely used in diagnosing insulinoma.
468
Beata Kos-Kudła et al.
The methods are practically used only when other
imaging techniques do not enable the locating of the
focal lesion [10]. In the near future, GLP-1 analogue
will probably play an important role in the diagnostics
of hardly detectable, small insulinomas, due to GLP-1
receptor expression in all tumours of this type.
2.5.2. Gastrinoma
Gastrinoma is found mostly within the triangle: pancreatic head — duodenum — hepatic hilum. In 48–60% of
cases, lymph nodes and hepatic metastases are present
at the diagnosis, but in some groups of patients, the
proportion of malignant neoplasms is up to 90% [104].
Multifocal lesions are also possible. The usefulness of
USG, EUS, intraoperative USG, IOUS, CT and MRI
examinations is presented in the section concerning
the imaging diagnostics of PNENs.
Other examinations used for the diagnostics of
gastrinoma include:
— somatostatin receptor scintigraphy (SRS). According
to different authors, the sensitivity of gastrinoma
detection ranges between 50% and 100% (according
to the literature data, the frequencies of expression
for different somatostatin receptors (SSTR) types
are as follows: SSTR1 — 71%, SSTR2 — 50%, SSTR3
— 92%, SSTR4 — 78%, SSTR5 — 81%) [105]. SRS is
the best examination to assess the early stages of the
disease and the presence of distant metastases, but
sensitivity of the test decreases to 50% if the tumour
is smaller than 1 cm [4];
— intraoperative radioisotope probe. This method
improves the sensitivity of detection of pancreatic
primary lesions and metastases to the surrounding
lymph nodes and to the liver;
— in the diagnostics of gastrinoma, scintigraphy with
the GLP-1 analogue may also be used, due to the
GLP-1 receptor expression in this tumour.
In the location diagnostics of small tumours, the
combined use of a few diagnostic methods seems
reasonable. In certain cases also performing angiography (the sensitivity of angiography is estimated
at 30-50%) with venous catheterisation (AVSV) may
be considered. In the case of gastrinoma located in
the duodenum, intraoperative transluminescence is
also used.
2.5.3. Location diagnostics of glucagonoma,
VIPoma, somatostatinoma, non-functioning
tumours and ACTHoma
At the moment of diagnosis, glucagonoma, somatostatinoma and NF-PNETs are usually large (approximately
5–6 cm), whereas VIPoma is slightly smaller (ca. 2 cm).
The lesions are usually diagnosed late, and in approximately 70–90% of cases metastases are found already at
Endokrynologia Polska 2013; 64 (6)
the diagnosis [16, 105]. Due to the size of lesions, they
are easier to find by means of classical imaging methods
(USG, CT, MRI). SRS, whose diagnostic sensitivity is
70–100%, is a standard examination in the assessment
of the primary lesion, clinical staging (detection of
metastases to the liver, lymph nodes, adrenal glands,
spine), and in qualification for receptor radiotherapy
[16, 86]. SSTR1 and SSTR2 expression is observed mostly
in glucagonoma, SSTR5 in somatostatinoma, SSTR2 in
VIPoma, and SSTR1, SSTR2, SSTR3 and SSTR5 in nonfunctioning neoplasms. Rare ACTHoma neoplasms
also demonstrate somatostatin receptor expression. In
the case of RF-PNENs, EUS is not recommended as the
first-line procedure, but it may be used when MDCT,
MRI and SRS-SPECT results are inconclusive. EUS may
be useful in pre-operative diagnostics, whereas it is
rarely necessary in patients with hepatic metastases [4].
2.5.4. Pancreatic endocrine carcinomas (PNECs)
In the location diagnostics of poorly differentiated
PNECs and their metastases, all imaging examinations
may be used: USG, CT, MRI, 18F-FDG PET, as well as
SRS in tumours with overexpression of somatostatin
receptors.
Summary of the diagnostics of PNENs
In the diagnostics of PNENs, both classical imaging
techniques and nuclear medicine tools are used. The
basic examination for patients with a PNEN is EUS,
which enables location of the primary tumour site.
Another examination is the SRS with 68Ga or 99Tc-DOTA
TOC, which enables location of the primary lesion, but
also assessment of the stage of the disease and qualification for treatment with ‘hot’ SSA. CT or MRI are next
in the diagnostics of PNENs; their main role consists
in the assessment of the stage of the disease. A PET/CT
scan with 18FDOPA may be an alternative diagnostic
method if SRS results are negative. In the diagnostics
of insulinoma, the role of a new isotope-labelled GLP-1
analogue is widely discussed.
Minimal consensus on imaging
The main examinations recommended in the diagnostics of
PNENs include: EUS, CT, and MR, and next a radioisotope
examination with a labelled somatostatin analogue (68Ga or
99
Tc-DOTA TOC PET/CT,SPECT/CT) (*evidence level 3).
3. Treatment of PNENs
3.1. Surgical treatment
Surgical treatment is the therapy of choice in the case of
PNENs, as it is associated with significantly prolonged
patient survival [2]. The development of diagnostic
methods has improved the detection of small, asymptomatic tumours. Most non-functional neoplasms
of ≤ 2 cm in diameter are benign and demonstrate
a moderate risk of becoming malignant. Only 6% of
non-functional, accidentally diagnosed PNENs present
histopathological characteristics of malignancy [2]. In
certain cases, tumours of ≤ 2 cm in diameter diagnosed
accidentally may be observed for the first year, performing tests at three-month intervals, then every six
months for the next three years [2]. Due to the lack of
clear recommendations, the decision on the course of
treatment should be taken by a multidisciplinary team
of doctors experienced in the management of PNENs
(*evidence level 4). When choosing surgical treatment,
it is necessary to consider short-term and long-term
effects of this therapy. According to the WHO classification, there is a correlation between the tumour size and
its potential malignancy. Tumours of > 2 cm require an
extensive surgery (*evidence level 3) [44].
In multiple endocrine neoplasia type 1 (MEN1), if
multiple lesions occur, it is recommended to remove
them preventively before they become malignant; however, this approach in the case of small, non-functional
neoplasms is still controversial (*evidence level 3) [2]. In
all cases, an intraoperative USG examination is recommended. The presence of multiple tumours sometimes
requires a whole-organ resection. It is known that nonfunctional neoplasms associated with MEN1 should
be removed if they are larger than 2 cm in diameter,
fast-growing (annual growth of > 0.5 cm), and if metastases occur [2].
The type of surgical treatment of PNEN depends on
its size, location, invasion of the adjacent organs, presence of distant metastases and the level of tumour malignancy, patient’s general condition and the ability to
control the clinical symptoms (*evidence level 4). Patients
are qualified for a radical or palliative treatment, which
only improves the quality of life (*evidence level 4). In
the case of tumours located in the head of the pancreas,
pancreatoduodenectomy is performed, whereas in tumours located in the body or tail of the pancreas, distal
resection is conducted, with or without splenectomy
(*evidence level 4). In certain cases of small and well-demarcated PNENs (non-functional neoplasms and insulinomas < 2 cm), atypical resections may be performed,
including enucleation and resection of the middle segment (*evidence level 3) [106]. Resection of the middle
segment is performed only in the case of small lesions
located in the pancreatic body. The condition of tumour
enucleation is continuity of the duct of Wirsung [2].
* evidence level according to CEBM [152]
469
Pancreatic neuroendocrine neoplasms
Resection is necessary if the tumour is located < 3 mm
from the pancreatic duct [4]. Enucleation of the lesion
entails the risk of damaging or closing the duct of
Wirsung, which is associated with complications [107].
These include acute postoperative pancreatitis and
pancreatic fistula. Apart from the above complications,
resection of a large part of the pancreas may cause the
symptoms of exocrine and endocrine pancreatic insufficiency [108]. In certain cases, it is possible to conduct
central pancreatectomy with a Roux-en-Y anastomosis
of the pancreatic tail with a loop of the small intestine,
and closing off the body of the pancreas.
Tumour resection should be considered even in the
presence of metastases, including hepatic metastases,
if they are potentially resectable, and the patient meets
the criteria for the surgery (*evidence level 4) [1, 44]. As
PNENs are often malignant, it is necessary to remove
the regional lymph nodes during resection (*evidence
level 3) [1, 108, 109]. In the case of enucleation and resection of the middle segment, it is also recommended
to remove lymph nodes for histopathological examination [2, 107]. It is generally believed that PNECs should
not be operated if disseminated metastases have been
found in the diagnostic process (*evidence level 3) [1].
Surgical treatment intended to remove the tumour
(in the case of a resectable tumour) or reduce its mass
(palliative therapy) in patients with disease limited to
the primary tumour and regional lymph nodes should
be standard procedure (*evidence level 4) [44]. Resection
should be performed only in those centres specialising
in surgery of the pancreas. Laparoscopic resection of
the pancreas is increasingly common, but the decision
concerning whether to use an ‘open’ or a laparoscopic
method should be taken by a pancreatic surgery specialist in the referential centre (*evidence level 3). Distal
resections and laparoscopic enucleation of pancreatic
tumours are presently considered to be safe [2]. In the
case of a PNEN, an intraoperative USG examination is
recommended.
The most common functional neoplasms are insulinoma and gastrinoma, while other tumours are rare
RF-PNENs [4]. Gastrinoma is most often located in
the head of the pancreas; in 60–90% it is a malignant
neoplasm, and due to a frequent invasion of the lymph
nodes, there are indications for regional lymphadenectomy [14]. It is recommended to remove the lesion radically to prevent hepatic metastases, which considerably
worsen the prognosis. The scope of procedures depends
on the tumour location and size, and comprises enucleations, resections of the middle segment, distal resections
and pancreatoduodenectomies [109]. Laparoscopic
* evidence level according to CEBM [152]
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Beata Kos-Kudła et al.
procedures are not recommended [4]. In ZollingerEllison syndrome (ZES), which may be associated with
MEN1 syndrome, surgical treatment is indicated if the
tumour is larger than 2 cm. This approach is intended
to prevent metastases [44] (*evidence level 3). Pancreatoduodenectomy is the recommended procedure (for
tumours located in the head of the pancreas), as less
extensive procedures are associated with recurrence
in 90% of cases [4, 14].
Insulinomas are in 90% of cases benign; their removal does not require regional lymphadenectomy
and where there is precise preoperative localisation of
the tumour, laparoscopy is effective [110]. In the case of
a suspected malignant insulinoma, or recurrence of the
tumour, radical treatment is recommended, including
excision of the recurrence and the possible hepatic metastases [4]. RF-PNEN include: VIPoma, glucagonoma,
somatostatinoma, GRHoma and ACTHoma. In this
group of tumours, radical surgical treatment is recommended even if hepatic metastases occur, and the scope
of resection and lymphadenectomy corresponds to the
procedures implemented in gastrinoma. Laparoscopic
procedures are not recommended (*evidence level 3)
[1, 4].
In advanced F-PNENs, resection is intended to
reduce the symptoms and the tumour mass. Cytoreduction may be considered if removal of 90% of the tumour
mass is possible, even if hepatic metastases are present.
Removal of 90% of the visible tumour mass is possible
in only 5–15% of cases [14, 111]. R1 resections of PNENs
are not associated with a worse survival rate than R0
resection [107]. Cytoreduction may be performed with
radiofrequency thermoablation (RFA) (*evidence level
3), which can also be conducted laparoscopically. This
method may be used if there are fewer than ten focal
lesions in the liver, and if the largest one is < 5 cm in
diameter (optimally 3 cm). This method enables the
control of symptoms in over 90% of patients [112].
Radical excision of hepatic metastases is the ‘gold
standard’ in the therapy of advanced PNENs, therefore
resection should be performed whenever it is possible
(*evidence level 4). The method of resection depends on
the patient’s general condition, and the size, location
and number of metastases. It comprises enucleation,
wedge excision of a fragment of the liver, excision of
a segment/segments, non-anatomical resection or hemihepatectomy. Resection of hepatic metastases of PNENs
is considered only in cases of G1 and G2 neoplasms
[113]. It depends on the resectability of the lymph
nodes, lack of micronodular or non-resectable dissemination in the peritoneum, or distant metastases outside
Endokrynologia Polska 2013; 64 (6)
of the abdominal cavity [113]. R2 resection should be
considered in selected cases of functional neoplasms
which do not respond to conservative treatment, in
order to reduce the intensity of the symptoms (*evidence
level 3). Excision of the primary tumour, lymph nodes
and hepatic metastases, combined with thermoablation, may reduce the tumour mass by more than 90%
[113]. In the case of unresectable metastatic lesions in
the liver, cholecystectomy should be performed during
surgery to prevent ischaemic complications of the gall
bladder resulting from a possible implementation of
(chemo) embolisation. Resection of hepatic lesions may
be performed in one or two stages, depending on the
location and size of the metastases [107]. Other methods
of treating metastases include locoregional therapies
(variants of ablation, embolisation) and liver transplantation. It is assumed that transplantation is conducted in
selected groups of patients with exacerbated symptoms
associated with hormonal secretion. Patients who may
benefit from transplantation are those under the age of
50, without metastases outside the liver, and with a low
expression of Ki-67 and E-cadherin [109].
If resection of hepatic metastases is impossible (unresectable or inoperable lesions), the recommended
treatment methods include hepatic artery embolisation (HAE), transarterial chemoembolisation (TACE) or
embolisation with the use of isotope (*evidence level 3).
Currently, these methods are considered to be safe [14].
RFA, cryoablation and microwave ablation (MWA) can
be used for tumours ≤ 5 cm [111].
In the case of a diagnosis of peritoneal dissemination, surgical treatment is controversial and is recommended only in a selected group of patients. Even in
some patients with unresectable liver disease, resection
of the primary tumour together with macroscopic intraperitoneal nodules makes it possible to focus further
therapies exclusively on the liver disease [114]. There is
no consensus on the simultaneous resection of hepatic
and intraperitoneal lesions. If an extensive surgery of
the liver with resection of peritoneal lesions is necessary, dividing the procedure into stages, conducting
the resection in a specialist centre, and introducing
multidirectional treatment should be considered. Presently, the combination of surgery and perioperative
intraperitoneal chemotherapy, as well as intraoperative
hyperthermic intraperitoneal chemotherapy (HIPEC)
are in the experimental phase [114].
If tumour resection and the elimination of symptoms
are not possible, a palliative surgical management is
implemented, which can significantly affect the quality of life. This is used after exhausting all non-surgical
methods, mainly when the tumour is responsible for
mechanical jaundice, chronic pain and gastrointestinal obstruction or bleeding. The treatment method is
individualised for each patient. If mechanical jaundice
occurs, it is recommended to perform anastomosis between the bile duct and intestine, or drainage of the bile
tract. When an unresectable pancreatic tumour disturbs
the passage of food through the duodenum, bypass
surgery is recommended, usually a gastrointestinal
anastomosis. The method of surgical management of
chronic pain is coeliac plexus neurolysis and/or thoracoscopic section of the splanchnic nerve. Treatment
of patients with PNEN should be comprehensive and
conducted by a multidisciplinary team of doctors; the
surgery should be performed in a centre specialising in
pancreatic surgery (*evidence level 3) [44].
Minimal consensus on surgical treatment
— Accidentally detected non-functional neoplasms of ≤ 2 cm
in diameter, without evidence of histopathological malignancy may be observed, and the decision on the course of
treatment should be taken by a multidisciplinary team
of doctors experienced in the management of PNENs.
Tumours of > 2 cm require an extensive surgery with
lymphadenectomy.
— In certain cases of small (< 2 cm) and well-demarcated
PNENs (non-functioning neoplasms and insulinomas),
atypical resections may be performed, including enucleation and resection of the middle segment (it is necessary
to collect the lymph nodes for histopathological examination). Distal resections and enucleations may be performed
laparoscopically.
— Tumour resection should be considered even in the presence of metastases, including hepatic metastases, if they
are potentially resectable and the patient meets the criteria
for the surgery. It is believed that PNECs should not be
operated if disseminated metastases have been found in
the diagnostic process.
— In advanced functioning PNENs, resection is intended to
reduce the symptoms and the tumour mass. Cytoreduction may be considered when the removal of 90% of the
tumour mass is possible, even if hepatic metastases are
present (*evidence level 3).
— In cases of unresectable hepatic metastases, the recommended palliative treatments include HAE, TACE
or embolisation with the use of a radioisotope. RFA,
cryoablation and MWA can be used in tumours ≤ 5 cm
(*evidence level 3).
Liver transplantation is conducted in a selected groups of
patients with exacerbated symptoms associated with hormonal
secretion. Patients who may benefit from the transplant are
* evidence level according to CEBM [152]
471
Pancreatic neuroendocrine neoplasms
those under the age of < 50 years, without metastases outside
the liver, and with a low expression of Ki-67 and E-cadherin
(*evidence level 3).
3.2. Endoscopic treatment of PNENs
The treatment of PNENs is generally surgical, and endoscopic management is only symptomatic.
Endoscopy may be used in the symptomatic treatment of:
— mechanical jaundice (prosthesis of the biliary duct);
— obstruction of the gastrointestinal tract (prosthesis
of the gastrointestinal tract lumen);
— control of gastrointestinal bleeding (the use of endoscopic hemostatic methods).
— EUS-controlled coeliac plexus neurolysis (CPN),
described for the first time in 1996, involving administration of 0.25% bupivacaine solution, followed by
98% alcohol, is an alternative method for the management of chronic pain associated with pancreatic
tumours [115].
In recent years, single cases of using EUS for ablation of F-PNETs secreting insulin have been reported
[116–118]. It is possible that in the future endoscopic
EUS-controlled ablation of PNETs, involving administration of cytotoxic agents, alcohol or using thermoablation will become a therapeutic method for patients who
cannot be treated surgically (*evidence level 4).
3.3. Medical treatment
The main purpose of pharmacological treatment is prevention of the symptoms of the disease and maintaining
the patient’s good quality of life (QoL) for the longest
possible time [44]. Prior to planning the treatment, the
tumour size, presence of metastases, histological grading and the profile of secreted peptides and markers
should be determined (*evidence level 4).
The choice of the treatment method depends on
the symptoms, staging of the disease, the level of radiotracer uptake in receptor scintigraphy and histological
characteristics of the tumour [119] (*evidence level 4).
For non-surgical NENs, the goal of the treatment
is alleviation of symptoms of the disease, maintaining optimal QoL and, if possible, prolonged survival
(*evidence level 5).
3.3.1. Symptomatic treatment
Symptomatic treatment should be started when the
clinical and biochemical symptoms indicate hormonal
activity of the NEN, even before the precise location
of the primary site or confirmation of metastases. The
symptoms associated with excessive secretion of hormones by PNENs may impair the patient’s quality of
* evidence level according to CEBM [152]
472
Beata Kos-Kudła et al.
life, and in certain cases they may be life-threatening
(e.g. severe diarrhoea and hypokalaemia in VIPoma or
carcinoid crisis).
Pharmacological treatment mostly involves somatostatin analogues and other medications, such as IPP
in gastrinoma or diazoxide in the case of insulinoma.
Additional symptomatic medications, such as loperamide, cholestyramine and corticosteroids are used if
necessary. Bisphosphonates can be used for pain management in patients with osseous metastases.
Functioning pancreatic neuroendocrine neoplasms
(F-PNENs)
Somatostatin analogues (SSA)
Using somatostatin analogues (octreotide, lanreotide)
is the ‘gold standard’ therapy of functioning PNENs,
regardless of the tumour size [1, 120]. The recently
published CLARINET study, involving 204 patients
with GEP NENs (45% of patients with PNENs), also
proved the antiproliferative effect of Lanreotide Autogel
in a randomised, placebo-controlled phase III trial [121]
(*evidence level 1).
New somatostatin analogues
SOM-230 (pasireotide) is a new analogue of somatostatin (SSA). In phase II studies, pasireotide was used for
symptomatic treatment in patients resistant to conventional therapy (octreotide and lanreotide).
Interferon α
Interferon α is used in the treatment of both functioning and non-functioning NENs, in monotherapy or
combined with long-acting SSA, if the patient does not
respond to the treatment with maximum SSA doses. Interferon α may also be used in symptomatic treatment,
but it is usually introduced as a second-line treatment
due to its unfavourable toxicity profile [1]. Sometimes
it is used as an adjuvant therapy in patients with clinical syndromes which cannot be controlled with SSA.
Insulinoma
Pharmacological treatment of insulinoma is intended to
prepare patients for a surgical procedure, or to achieve
biochemical control in patients with inoperable metastatic insulinoma. Apart from frequent meals of small
volume, patients require intravenous glucose administration. Despite this treatment, hypoglycaemia often
requires additional medications to control the serum
glucose concentration. In most patients with insulinoma, diaxozide has proved to be effective in controlling
the symptoms of hypoglycaemia [4]. Diazoxide is used
for short-term treatment of patients with insulinoma
awaiting surgery, or for long-term treatment of patients
with inoperable tumours. Diazoxide is an antihypertensive medication with an additional hyperglycaemic
Endokrynologia Polska 2013; 64 (6)
effect, as it inhibits insulin secretion by a direct action
on pancreatic β cells and activation of glycogenolysis.
The recommended daily dose is 50–300 mg orally, up
to 600 mg/d. This is usually an effective treatment in
controlling the symptoms of hypoglycaemia in patients
with insulinoma. Adverse events, including oedema,
increased body weight, hirsutism and renal function
disorders are common, but usually tolerable.
Diazoxide therapy is often supported with hydrochlorothiazide at a dose of 25 mg/day, which prevents
oedema, hyperkalaemia and increases the hyperglycaemic effect of diazoxide.
Verapamil and diphenylhydantoin (phenytoin) can
be used to control glycaemia, as an alternative to diazoxide, in some patients with insulinoma. Corticosteroids,
including prednisolone, are usually used in insulinoma
patients resistant to the treatment of hypoglycaemia.
SSA (octreotide and lanreotide) are used in patients
with confirmed somatostatin receptor type 2 expression
on the tumour cells [119]. They are often ineffective in
controlling hypoglycaemia (50–60% of insulinomas)
and their effect on the blood glucose concentration
varies [122]. In some cases, they may even intensify
hypoglycaemia by inhibiting glucagon secretion [4, 123].
In some patients, using interferon α may be beneficial in treating hypoglycaemia [34]. An mTOR inhibitor — everolimus — is one of the medicines controlling
insulin secretion and hypoglycaemia in patients with
malignant insulinoma [4].
Gastrinoma
Pharmacological treatment of gastrinoma is discussed in the section on gastroduodenal NENs (pp.
444–458).
VIPoma (symptoms: watery diarrhoea, hypokalaemia,
achlorhydria (WDHA), Verner-Morrison syndrome)
Hydration and supplementation of electrolytes
is recommended, as they may considerably improve
the patient’s clinical condition. In patients with
VIPoma, accompanied by a rare life-threatening syndrome, administration of SSA significantly relieves
the symptoms (in 80–90% of patients) and lowers
the concentration of vasoactive intestinal peptide
(60–80%) [124]. Biochemical improvement does not
always correlate with clinical improvement, so a
dose titration based on patient’s clinical condition is
necessary. Corticosteroids are used in patients with
life-threatening diarrhoea which does not respond
to the maximum doses of SSA.
Glucagonoma
Following introduction of SSA treatment, 80–90% of
patients with glucagonoma demonstrate a visible clini-
cal improvement (reduced skin lesions due to necrolytic
erythema), although the treatment is less effective in
controlling diabetes and weight loss. SSA reduces
blood glucagon concentration in approximately 60%
of patients, although normalisation of this parameter
is unlikely [125].
Zinc salts may be used in patients with glucagonoma to prevent further skin damage. Antithrombotic
prophylaxis should be considered in all patients with
NEN associated with an increased risk of thromboembolic complications (e.g. glucagonoma).
Long-acting SSA are also effective in fighting the
symptoms of ectopic hypersecretion in some cases of
somatostatinoma [4]. They may also be useful in patients with paraneoplastic syndromes, e.g. Cushing’s
syndrome and acromegaly, associated with ectopic
secretion of ACTH or the growth-hormone-releasing
hormone (GHRH).
In recent years, there has been growing interest
in the use of glucocorticosteroid receptor antagonists,
e.g. mifepristone, as well as dopamine agonists, e.g.
cabergoline, in the treatment of Cushing’s syndrome.
SSA have been proven effective in controlling hypercalcaemia associated with the hypersecretion of the
parathyroid hormone-related peptide (PTHrP) in rare
PNENs secreting PTHrH [126].
Non-functioning pancreatic neuroendocrine
neoplasms (NF-PNENs)
Somatostatin analogues demonstrate antiproliferative effects, confirmed in patients with NENs. PROMID
was the first phase III study, which revealed such effects
of octreotide in the midgut tumours, both functioning and non-functioning ones [127]. In patients with
PNENs, observational studies have demonstrated partial or complete response in less than 10% of patients,
and radiological stabilisation of the neoplasm in 24–57%
of patients [128–130]. The results of the CLARINET
phase III study have confirmed the antiproliferative
effect of Lanreotide Autogel in patients with nonfunctioning PNETs with low proliferation index (Ki-67
< 10%) [121, 131].
3.3.2. Chemotherapy and targeted treatment
Chemotherapy is discussed in detail in section I of
"Diagnostic and therapeutic guidelines for gastroentero-pancreatic neuroendocrine neoplasms
(recommended by the Polish Network of Neuroendocrine Tumors)" (pp. 418–443)
Given the present state of knowledge, there is no evidence that any adjuvant therapy (i.e. additional therapy
after radical surgery) has a positive effect on extend-
* evidence level according to CEBM [152]
473
Pancreatic neuroendocrine neoplasms
ing disease-free survival (DFS) and/or overall survival
(OS) of patients with PNENs. This applies primarily to
G1/G2 NENs [132]. In the case of neuroendocrine carcinoma (NEC), an adjuvant therapy based on platinum
analogues should be considered. Although there are no
phase III randomised prospective studies, it seems that
chemotherapy including cisplatin (or carboplatin) with
etoposide may prolong disease-free survival in patients
with NECs (*evidence level 4). The use of adjuvant radiotherapy or radiochemotherapy is not scientifically
supported.
In patients with advanced NECs, the basic therapy
is chemotherapy including platinum analogues plus
etoposide [132] (*evidence level 3).
The best results in the chemotherapy of advanced
NENs have been achieved in G1/G2 NETs of pancreatic
origin. The use of streptozotocin (STZ) in monotherapy
resulted in a response rate (RR) of approximately 36%,
and OS of ca. 17 months. Combining streptozotocin with
5-fluorouracil (5-FU) increased the response rate to 63%
and extended the mean overall survival to 26 months
[133]. A breakthrough in chemotherapy of G1/G2 NENs
was the phase III study by Moertel et al. in 1992 [134], in
which 69 patients were randomised to two chemotherapy
arms: streptozotocin-based, i.e. with doxorubicin (DOX)
v. chemotherapy with 5-FU, demonstrating RR of 69% v.
45%, respectively, with the mean clinical response time of
18 months v. 14 months, and the mean overall survival of
26 months v. 17 months (*evidence level 3).
The effectiveness of the chemotherapy of well/medium-differentiated GEP NENs should be considered
separately for neoplasms of pancreatic origin and those
with different locations (stomach, duodenum, small
intestine, appendix and colon). Indirect comparisons
of the results of clinical studies involving patients with
GEP NENs have demonstrated a higher probability of
response in patients treated due to PNENs (15–35%
compared to 5–15%) [135].
In well-differentiated PNENs, the highest activity in
monotherapy (response rate: 20–40%) is demonstrated
by streptozotocin, doxorubicin, fluorouracil, dacarbazine and temozolomide. Multi-drug regimens are
more effective then monotherapy regarding the effect
on the response and survival rates (mean survival —
15–30 months).
The expert panel recommends combining streptozotocin (the medicine is not registered in Poland, available
as direct import) with doxorubicin and 5-fluorouracil,
and using a two-drug chemotherapy in patients with
a greater risk of complications or not qualifying for the
treatment with anthracyclines.
* evidence level according to CEBM [152]
474
Beata Kos-Kudła et al.
3.2.3. New targeted therapies [44]
In patients diagnosed with advanced PNENs (locally
advanced stage, without a possibility of surgical
treatment and disseminated stage), it is now possible to use molecularly targeted drugs (sunitinib and
everolimus) in the case of progression of the disease
(progression within the last 12 months assessed on
the basis of imaging examinations results and the
RECIST classification). Sunitinib is indicated in the
case of well-differentiated neoplasms (NENG1), and
indications for everolimus comprise well- and moderately-differentiated neoplasms (NENG1 and NENG2)
[136, 137]. These medications — everolimus (a serine/
/threonine kinase — mTOR — inhibitor) and sunitinib
(a tyrosine-kinase inhibitor) [138] significantly extend
progression-free survival (PFS) by approximately
5.5–6 months. Adding everolimus to octreotide (the
RADIANT-3 trial) extended progression-free survival
by approximately five months (16.4 v. 11.3) compared
to monotherapy with SST analogue.
In patients with malignant insulinomas resistant to
conventional treatment, using everolimus significantly
improved the control of glycaemia [139, 140].
Everolimus and sunitinib may, in justifiable cases,
be used as the first-line treatment in patients with advanced well-differentiated PNENs (documented radiological progression within 12 months) (*evidence level 1).
Using sunitinib and everolimus is associated with
a number of unresolved problems (e.g. the order of use
for various treatment methods, selection of patients for
specific medications, the ability to anticipate effectiveness, and adverse reactions). The value of sunitinib
and everolimus in poorly differentiated PNECs, and
the possibility of combining them with other methods
(e.g. adjuvant postsurgical treatment) also require
clarification.
The effectiveness of pazopanib (another multikinase
inhibitor), demonstrated in the phase II studies, needs
to be confirmed, which is particularly important due to
a generally better tolerance of the treatment.
Minimal consensus on the medical treatment in
pancreatic NENs
Functioning G1/G2 PNENs — somatostatin analogues (*evidence level 1), and in the case of progression of the disease,
adding everolimus (*evidence level 1).
Advanced non-functioning G1/G2 PNENs — systemic
chemotherapy including streptozotocin with doxorubicin
(± 5-FU) (*evidence level 3) and/or a somatostatin analogue
(*evidence level 1). If the disease progresses after chemotherapy, everolimus or sunitinib (*evidence level 1). Targeted
Endokrynologia Polska 2013; 64 (6)
therapy can be considered as first-line therapy in selected cases
as an alternative treatment to chemotherapy.
The basic treatment of PNEC is chemotherapy based on the
cisplatin plus etoposide regimen (*evidence level 3).
3.4. Radioisotope treatment
Isotope therapy with labelled SSA (PRRT, peptide
receptor radionuclide therapy) is now becoming a recognised form of palliative treatment, giving a chance
for stabilisation or partial regression of the neoplastic
disease, and less often for a complete remission [141,
142]. De Jong et al. [141] in 1998 published the results
of a multicentre study involving a group of 256 patients
with GEP NENs, including PNENs, treated with 90Y
DOTA TOC.
In 27% of the patients, a partial response to the
treatment was observed, and in individual cases
a total response was achieved. The results of the
90
Y/177Lu DOTA TOC therapy in a group of 20 patients, including 15 with PNEN, were presented in
2006. Regarding the patients with PNEN, the authors
observed stabilisation of the disease in eight patients,
partial remission in four patients, and progression of
the disease in three patients [143]. Presently, more
common in PRRT is [Tyr3]octreotate (DOTA TATE),
an analogue which demonstrates a higher affinity to
SSTR2 than the previously used ones. The therapy
has been successfully conducted in a few centres in
Poland, also in patients with PNENs, after confirming a high somatostatin receptor expression in the
primary/meta tumour in SPECT or PET examination.
It is now believed that, similarly to GEP NEN of
different locations, the therapy may be introduced
without a prior chemotherapy. Based on the observations in patients treated with chemotherapy before
the isotope treatment, is has been established that
myelotoxicity and nephrotoxicity occur more often.
Similarly to other GEP NENs, the main indications for the treatment of PNEN with labelled SSA
are advanced and inoperable NENG1 or NENG2. In
individual cases, this therapy may be used in NEC with
a sufficient somatostatin receptor expression, especially
if the disease progresses and other treatment options
have been exhausted [2, 4, 34]. Isotope therapy may be
considered in the case of non-surgical recurrence and
primarily, as a form of neoadjuvant treatment if surgical management is impossible due to a significant local
advancement of the tumour [144]. Recent reports point
to the possibility of using PRRT much earlier, before
the surgery of unresectable lesions, mostly in the case
of PNENs. The authors used both 90Y and 177Lu isotope
combined with a SSA. Among the patients receiving
PRRT as noeoadjuvant treatment of an inoperable
primary tumour, there were single cases of patients
with hepatic metastases, in whom the isotope therapy
resulted not only in regression of the tumour mass,
but also of the metastatic lesions [145, 146]. Due to
a limited group of patients receiving this form of treatment, there is no strong evidence for introducing PRRT
prior to a non-surgical procedure in the management
guidelines; however, this form of treatment may be
individually considered, depending on the patient’s
clinical condition, advancement of the disease and the
proliferation index of the neoplasm. Each time while
deciding on the isotope treatment, adverse reactions associated with this form of therapy should be taken into
account. In the case of PNENs with insufficient SSTR2
expression, indications for the 90Y and 177Lu DOTA TATE
therapy may be limited. In overexpression of SSTR5,
another radiotracer, i.e. 90Y DOTA LAN may be used
[34]. Expression of this type of receptor may also be
present in well-differentiated neoplasms, especially
those which lost the active SSTR2 during therapy, as
a result of treatment with SSA (tachyphylaxis) [34].
PRRT may also be used to treat functioning PNENs.
In the case of malignant lesions, it is possible to
conduct isotope treatment [10, 34] as a form of palliative management with temporary therapeutic
response. In patients with diffuse gastrin tumour and
positive receptor scintigraphy results, eligibility for
PRRT should be considered. However, similarly to
other PNENs, this therapy requires studies involving
a larger number of patients in order to establish its
actual therapeutic value [104]. Based on individual
reports in the literature, it is known that gastrinomas
respond to therapy faster, but early progression is
relatively frequent [34].
The treatment with ‘hot’ SSA is a relatively new form
of therapy, used mainly as palliative treatment, without any expectations regarding the impact on partial
remission of the disease or the patient’s survival. Some
new publications have indicated a possibility of using
PRRT as second-line therapy in the case of disease progression, following stabilisation or remission achieved
with this method. It appears that re-implementation of
isotope treatment at the maintained expression of somatostatin receptors may prolong the patient’s survival
without a significant exacerbation of adverse reactions
associated with this therapy [147]. Radioisotope treatment is frequently combined with ‘cold’ SSA (including
non-functioning neoplasms). Monitoring of the effects
of PRRT comprises not only imaging examinations,
* evidence level according to CEBM [152]
475
Pancreatic neuroendocrine neoplasms
but also monitoring of CgA and the markers specific
for functioning PNENs. In PNEN, CgA is a prognostic
factor of PFS [148].
Among different forms of PRRT in NETs, including PNENs, radioembolisation with yttrium-labelled
microspheres is used, in which the response rate
is estimated at 52–66% and the mean survival is
70 months [149, 150]. According to Ramage et al. [151],
a complete remission of the disease is achieved in
2.7% of patients, and a partial remission in 60%. Since
there are no reports on the use of radioembolisation
in a larger group of patients, further studies in this
field are necessary.
Beata Kos-Kudła et al.
Minimal consensus on follow-up
Monitoring of the treatment should be individualised according to histological differentiation of the NEN (G1, G2 or G3)
and the disease staging.
Follow-up comprises clinical examination, determination
of the concentration of CgA and specific markers (in functioning neoplasms, depending on the clinical symptoms), as well
as radiological (USG, CT/MRI), endoscopic and functioning
(SRS) examinations. The frequency of examinations depends
on the stage of the disease (2–3 months for NECs and 6–12
months for G1 and G2 PNETs).
References
Position of PRRT in the management of PNENs
In both functioning and non-functioning PNENs,
the basic form of treatment is surgery. In the case of
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Chemotherapy may be introduced as the second-line
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SSTR expression is lost.
The next stage in the management of secreting tumours progressing after the surgical treatment is using
‘cold’ SSA. Isotope treatment should be considered as
the second-line treatment.
Minimal consensus on PRRT
PRRT may be used in advanced, inoperable PNENs, especially
G2 and G1 (*evidence level 3). PRRT may be considered in
individual cases with NEC, provided a high somatostatin
receptor expression is confirmed and other forms of therapy
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In functioning neoplasms of the pancreas, PRRT as the
second line treatment, after a ‘cold’ SSA (*evidence level 3).
In non-functioning tumours of the pancreas, PRRT may
be considered as the first-line therapy, preceding other forms
of palliative treatment (*evidence level 4).
In both cases, surgical management is the basic form of
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OCEBM Levels of Evidence Working Group*. "The Oxford 2011 Levels
of Evidence". Oxford Centre for Evidence-Based Medicine. http://www.
cebm.net/index.aspx?o=5653 * OCEBM Table of Evidence Working
Group = Jeremy Howick, Iain Chalmers (James Lind Library), Paul
Glasziou, Trish Greenhalgh, Carl Heneghan, Alessandro Liberati, Ivan
Moschetti, Bob Phillips, Hazel Thornton, Olive Goddard and Mary
Hodgkinson.
List of Participants of the Consensus Conference on the 2013
Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms:
Elżbieta Andrysiak-Mamos (Department of Endocrinology,
Metabolic Diseases and Internal Diseases, Pomeranian Medical
University, Szczecin, Poland), Tomasz Bednarczuk (Department
of Internal Medicine and Endocrinology, Medical University of
Warsaw, Warsaw, Poland), Jolanta Blicharz-Dorniak (Division
of Endocrinology, Medical University of Silesia, Katowice,
Poland), Marek Bolanowski (Department of Endocrinology,
Diabetology and Isotope Therapy, Medical University of Wroclaw,
Wroclaw, Poland), Andrzej Cichocki (Department of Oncological
Surgery, Maria Skłodowska-Curie Memorial Cancer Center and
Institute of Oncology, Warsaw Branch, Poland), Jarosław B.
Ćwikła (Department of Radiology, Faculty of Medical Science,
University of Varmia and Masuria, Olsztyn, Poland), Andrzej
Deptała (Department of Oncology and Hematology, Central
Clinical Hospital of the Ministry of Interior in Warsaw, Warsaw,
Poland), Wanda Foltyn (Division of Endocrinology, Department
of Pathophysiology and Endocrinology, Medical University of
Silesia, Katowice), Daria Handkiewicz-Junak (Department of
Nuclear Medicine and Endocrine Oncology, Maria SkłodowskaCurie Memorial Cancer Center and Institute of Oncology, Gliwice
Branch, Poland), Marek Hartleb (Department of Gastroenterology
and Hepatology, Medical University of Silesia, Katowice, Poland),
Michał Jarząb (Department of Radiotherapy and Chemotherapy,
Maria Skłodowska-Curie Memorial Cancer Center and Institute
of Oncology, Gliwice Branch, Poland), Arkadiusz Jeziorski
(Department of Surgical Oncology, Medical University of Lodz,
Lodz, Poland), Dariusz Kajdaniuk (Division ofPathophysiology,
Department of Pathophysiology and Endocrinology, Medical
University of Silesia, Katowice, Poland), Grzegorz Kamiński
(Department of Endocrinology and Radioisotopic Therapy,
Military Institute of Medicine, Warsaw, Poland), Aldona Kowalska
(Department of Endocrinology, Holycross Cancer Centre, Kielce,
Poland), Robert Król (Department of General, Vascular and
Transplant Surgery, Medical University of Silesia, Katowice,
Poland), Leszek Królicki (Nuclear Medicine Department, Medical
University of Warsaw, Warsaw, Poland), Jolanta Kunikowska
(Nuclear Medicine Department, Medical University of Warsaw,
Warsaw, Poland), Dariusz Lange (Department of Tumour Pathology,
Maria Skłodowska-Curie Memorial Cancer Center and Institute of
Oncology, Gliwice Branch, Poland), Anna Lewczuk (Department
of Endocrinology and Internal Medicine, Medical University
of Gdansk, Poland), Magdalena Londzin-Olesik (Division of
Endocrinology, Medical University of Silesia, Katowice, Poland),
Przemysław Majewski (Department of Clinical Pathomorphology,
Poznan University of Medical Sciences, Poznan, Poland),
Gabriela Mełeń-Mucha (Department of Immunoendocrinology,
Chair of Endocrinology, Medical University of Lodz, Lodz,
Poland), Andrzej Nowak (Department of Gastroenterology and
Hepatology, Medical University of Silesia, Katowice, Poland),
Waldemar Patkowski (Department of General, Transplant and
Liver Surgery, Medical University of Warsaw, Warsaw, Poland),
Marek Ruchała (Department of Endocrinology, Metabolism
and Internal Medicine, Poznan University of Medical Sciences,
Poznan, Poland), Sławomir Rudzki (Department of General and
Transplant Surgery and Nutritional Treatment, Medical University
of Lublin, Lublin, Poland), Philippe Ruszniewski (Department
of Gastroenterology, Hospital Beaujon, AP-HP, University Paris
VII, Clichy, France), Grażyna Rydzewska (Clinical Department
of Internal Medicine and Gastroenterology, Central Clinical
Hospital Ministry of Interior, Warsaw, Poland), Teresa Starzyńska
(Department of Gastroenterology, Pomeranian Medical University,
Szczecin, Poland), Katarzyna Steinhof-Radwańska (Department
of Radiology, Medical University of Silesia, Katowice, Poland),
Janusz Strzelczyk (Division of Endocrinology, Department of
Pathophysiology and Endocrinology, Medical University of Silesia,
Katowice, Poland), Wojciech Zajęcki (Division of Endocrinology,
Medical University of Silesia, Katowice, Poland), Piotr Zdunowski
(Department of Endocrinology, The Centre of Postgraduate
Medical Education, Warsaw, Poland), Anna Zemczak (Division of
Endocrinology, Medical University of Silesia, Katowice, Poland).
479