pancreatic neuro endocrinr tumours

1. Pancreatic Neuro-endocrine
Tumours

2. – NETs arise from cells which produce and secrete hormones
– Most NETs are slow growing and malignant, with metastatic potential
– Common sites of origin are:
• GI tract
• Lungs
• Pancreas
2
Introduction to NETs

3. 3
WHO Classification for NET
Ong SL, et al. Pancreatology. 2009;9:583-600.
Neuroendocrine
Tumours
Site of Origin
• GI tract
• Pancreas
• Lungs
• Thyroid
• Pituitary
• Others
Malignant Potential
• Benign
• Benign or low
malignant potential
(uncertain)
• Low malignant
potential
• Highly malignant
Functional Activity
• Functioning
• Non-Functioning

4. The Pancreas Is the Most Common Primary Location of NET
Breakdown in Middle East & Asia Pacific Region
Stomach 6%
Liver 4%
Bile duct and gallbladder 3%
Omentum/abdominal lining 1%
Rectum 1%
Ovary 1%
Lung 1%
Hwang T, et al. Presented at: 8th Annual ENETS Conference; March 9-11, 2011; Lisbon, Portugal. Abstract C48.

5. Pancreatic neuroendocrine tumors
(pNET)
• Pancreatic endocrine tumors, islet cell carcinoma, or
pancreatic carcinoid
• Low - to intermediate-grade neoplasms and have a more
indolent course compared to pancreatic adenocarcinoma
• Functional if they are associated with a hormonal syndrome
– Disease bulk
– Stage
– Secretory status
– Whether the peptide secreted is intact and causes distinct
clinical symptoms
– Functional status of these tumors may change over time or with
treatment

6. • Majority of pNETs are malignant, with the
exception of insulinomas, which are benign in
95% of patients

7. EPIDEMIOLOGY
• Relatively rare neoplasms
• 2%-10% of all pancreatic tumors
• Incidence and prevalence are somewhat elusive
• Age-adjusted incidence of pNETs has risen significantly over
the last three decades
– Better diagnosis and
– Classification
– Environmental factors including the use of certain medications
• Incidence of pNETs in the United States was estimated to
be 5.6 per million in 2010
• Prevalen ce of small asymptomatic islet cell tumors may be
100-fold more common

8. • Slightly more common among men (53%) than women
(47%)
• Median age at diagnosis was 60 years
• At diagnosis,
– 14% had localized disease,
– 22% had regional disease, and
– 64% had distant disease.
• The survival of patients with pNETs has improved over
time
• 1988 through 2004, the 5-year survival rates among
patients with localized, regional, an distant pNETs were
79%, 62%, and 27%, respectively

9. Pathology
• Tumors arise from islets or ducts ???
– Transgenic mice expressing potent oncogenes in
endocrine cells and multiple endocrine neoplasia
(MEN)1 knockout mice point to an islet origin of
tumors
– Molecular evidence from islet microdissection in
patients with MEN1 indicate a duct cell origin
– Endocrine tumor cells largely display the same
phenotype as their normal endocrine counterpart

10. • Multiple Endocrine Neoplasia Type 1
– Tumor size may not be a completely reliable predictor
of malignant behavior, as metastatic disease may be
present in patients with MEN1 even when the primary
tumors are small
– Thompson was the first to advocate a specific surgical
procedure in patients with MEN1 with nonfunctioning
pNETs >1 cm in diameter to include distal subtotal
pancreatectomy, enucleation of any identified lesions
in the pancreatic head or uncinate process, and
regional lymphadenectomy

11. • Tuberous Sclerosis
– The genes responsible for tuberous sclerosis, TSC-1
and TSC-2, are located on chromosomes 9q34 and
16p13.3, respectively, and code for the proteins
hamartin and tuberin
– TSC1/2 complex is an inhibitor of mTOR
• Neurofibromatosis
– Von Recklinghausen disease, is an autosomal
dominant disease
– Protein neurofibromin 1 and is located on
chromosome 17
– NF1 is associated with the development of NETs in the
region of the duodenum and ampulla of Vater
– Endocrine tumors that arise from Von Recklinghausen
disease (NF1) are somatostatinomas

12. • Von Hippel-Lindau Syndrome
– Autosomal dominant
– Retinal, cerebellar, and spinal hemangioblastoma,
as well as renal cell carcinoma,
pheochromocytoma, and pNETs
– vHL gene is located on chromosome 3p26-p25
– pNETs occur in approximately 15% of patients with
VHL

13. 2010 World Health Organization (WHO) classification
• Well-differentiated tumors
– Trabecular, glandular, acinar, or mixed structures; the stroma is
generally fine and rich in welldeveloped blood vessels,
sometimes with hyalinised deposits of amyloid; tumor cells are
monomorphic with abundant, variably eosinophilic cytoplasm,
low cytological atypia and low mitotic index.
– Necrosis is usually absent or may be seen as spotty, limited
areas in histologically more aggressive neoplasms
– Neuroendocrine tumor
• Poorly differentiated neuroendocrine carcinomas
– Prevalent solid structure with abundant necrosis, often central,
round tumor cell of small to medium size with severe cellular
atypia and high mitotic index
– Neuroendocrine carcinoma

14. • Diagnosis of pNET is necessary
(1) to meet the previously defined histologic and
cytologic criteria,
(2) to assess the status of endocrine differentiation,
and
(3) to evaluate prognostic markers (proliferative
index).

15. • Fine Needle Aspiration Versus Core Needle Biopsy
– FNAC
• Simplicity, low invasiveness, and cost
• Disadvantages -operator-dependent efficacy and limited
option for further study (small sample size) to include
prognostic variables.
– Core needle biopsy (ideally 2 mm in diameter)
• Larger sized tumor sample - cyto-/histologic diagnosis
complete with all known prognostic parameters.
• Potential for further studies to include all IHC studies and
assessment of proliferative index.
• Disadvantages are the invasiveness of the procedure(s) and
the relatively higher costs
– core needle when considering biopsy of liver
metastases and FNA for biopsy of the pancreas.

16. • Immunohistochemistry Markers
– (1) positively identify the degree of endocrine
differentiation in tumor cells, and (2) determining the
proliferation activity status.
– General markers
• Neuron-specific enolase (NSE)
• Chromogranin A [CgA]
• Synaptophysin
– Hormones and/or amines are produced by specific cell
types - specific markers
– Proliferation status is achieved by Ki67 IHC using the MIB1
antibody or it can be expressed as mitoses per 10 high
power microscopic fields (or 2 mm2)

18. • Low (G1) and intermediate (G2) grade neoplasms
are termed pNETs
• Aggressive high-grade (G3) neoplasm are termed
pancreatic neuroendocrine carcinoma
• Optimal Ki-67 cut-off between G1 and G2
remains debated in the literature.
• Some authors have proposed 5% (instead of 2%)
as a more discriminatory cut-point for important
outcomes including overall survival (OS)
• distinction between G1 and G2, while prognostic,
does not have major therapeutic implications

19. • Platinum-based chemotherapy is generally
recommended for G3 tumors
• Response rate to platinum-based
chemotherapy was low for the subgroup of G3
patients with Ki-67 between 20% and 55%.
• Tumors with a Ki-67 >55% appear more
responsive to platinum-based chemotherapy

20. Molecular Genetics of Pancreatic Neuroendocrine Tumors
• Exome sequencing studies identified three
main groups (pathways) of mutations in
sporadic - MEN1, DAXX or ATRX, and
mammalian target of rapamycin (mTOR)

21. • Nonfunctional Tumors
• 60%-80% of pancreatic NETs as non-functional
• Symptoms
– Usually asymptomatic
– The tumor bulk results in pain
• Invasion of the autonomic mesenteric plexus
• Liver metastases that invade the liver capsule
• Extend to the parietal peritoneum
– Jaundice due process-obstruction of the intrapancreatic
portion of the common bile ductto - right of the superior
mesenteric vessels -head or uncinate
– Gastric outlet obstruction
– Gastrointestinal hemorrhage secondary to tumor erosion
into the duodenum or secondary to splenic vein
occlusion causing gastroesophageal varices (sinistral
portal hypertension)

22. • pNETs arising to the left of the SMA and
superior mesenteric vein may cause vague,
poorly localized upper abdominal pain or
dyspepsia, but such tumors are usually
asymptomatic until they reach a considerable
size

23. • Computed tomography (CT)
– Characteristically appear hyperdense, as they are
hypervascular
– During the arterial phase is critically important to
detect these lesions and their hypervascular liver
metastases
– Occasionally appear hypodense compared with
adjacent pancreatic parenchyma, and they may
contain cystic components or microcalcifications
– Intrapancreatic accessory splenic tissue can present as
an asymptomatic, hypervascular mass involving the
distal pancreatic tail, thus mimicking a pNET

24. • Magnetic resonance imaging (MRI)
– Patients with a history of allergy to iodine contrast
material
– Renal insufficiency
– More sensitive than CT for the detection of small liver
metastases
• Endoscopic ultrasound (EUS)
– Most sensitive modality for identifying small pNETs
– Used for preoperative tumor localization in patients
with MEN1, in which multifocal disease is common
– FNA biopsy of the tumor

25. • Serum Tumor Markers
– Evaluated for the diagnosis and follow-up
management of pNETs
– General markers
– CgA - 49-kDa acidic polypeptide
• Present in the secretory granules of neuroendocrine
cells
• Elevated in the majority of patients with either
functioning or nonfunctioning pNETs
• Prognostic – decreased during therapy has increased
progress free survival

26. • NSE, is a dimmer of the glycolytic enzyme enolase
– Less specific as a diagnostic marker, it may be helpful in
the follow-up of patients with unresectable disease
• PP- at least three times the age-matched normal basal
level obtained in a fasting state
• Chromogranins such as chromogranin B and C,
pancreastatin, substance P, neurotensin, neurokinin A,
gastrin, glucagon, vasoactive intestinal peptide, insulin,
proinsulin, and cpeptide.
• In general, blood markers should be drawn in the
fasting state

27. Somatostatin receptor scinitigraphy
• Octreotide conjugated with diethylene-triamine-
pentaacetic acid (DTPA) and labeled with 111In is a
radiolabeled somatostatin analog with great
affinity for sstr2 and widely used in clinical practic
• 68Ga PET/CT is becoming the new gold standard
for somatostatin receptor imaging of PNET. The
sensitivity of this technique varies between 91
and 95% with a specificity of 82-97%
• Functional imaging with positron emission
tomography (PET) are (68)Ga-DOTATATE and
(68)Ga-DOTATOC

28. • Nuclear scans

29. Surgical Treatment
• Goals of surgery are to maximize local disease control
and to increase the quality and length of patient
survival
• Resect localized, nonmetastatic disease confined to the
pancreas if a gross complete resection can be
performed
• If radiographically occult liver metastases are found at
the time of the operation, they are removed if possible
• If the liver metastases are of small volume but diffuse,
the primary tumor is usually removed due to the
potential for major morbidity from the primary, which
is a possibility because of the relatively long-
anticipated survival of the patient

30. • Nonfunctioning pNETs < (approximately) 2 cm in
diameter are of limited metastatic potential
• Observation may be the best approach
– Patients of advanced age
– Clinically significant comorbiditie
– Incidental finding on CT/MRI obtained for an
unrelated reason
– Repeat imaging in 6 to 12 months
– Observation is chosen - functional study such as
somatostatin receptor scintingraphy

31. • Metastatic disease or a large, borderline resectable
primary tumor, we would first initiate systemic therapy
as a bridge to eventual operation.
• Significant downstaging of the overall tumor burden
can improve the safety of surgery in some patients
• Rationale for aggressive management of the primary
tumor despite the presence of extrapancreatic disease
may become more compelling.
• However, treatment sequencing will likely emphasize a
surgery-last strategy (after induction systemic therapy)
to identify those patients most likely to benefit from
large, multiorgan resections
• Resectable primary tumor and resectable liver
metastases.
– Remove the pancreatic tumor first
– Resecting the liver under the same anesthesia induction or
two-stage procedure if all needed surgery cannot safely be
performed at one operation

32. • Because of the longer survival times of
patients with pNETs (even advanced disease),
we favor operative bypass of the bile duct and
duodenum in most cases.

33. Advanced Pancreatic Neuroendocrine Tumors
• Goals of oncologic management include palliation
or prevention of symptoms and cytoreduction of
bulky tumors in an effort to prolong survival
• Cytotoxic chemotherapy,
• Everolimus,
• Sunitinib,
• Somatostatin analogues,
• Peptide-receptor radiotherapy, as well as
• Ablative approaches such as hepatic artery
embolization and radiofrequency ablation (RFA)

34. • Somatostatin Analogues
– Octreotide and lanreotide both bind with high
affinity to SSTR 2 and with slightly lower affinity to
SSTR 5.
– Pasireotide is a novel cyclohexapeptide in
development that binds to SSRT 1, 2, 3, and 5
– Approved for the control of symptoms related to
hormonal hypersecretion in NETs
– Associated with significant benefit in PFS

35. – Somatostatin (SST)
receptors are highly
expressed on the surface
of GI NETs
• More than 80% of all
NETs express SST
receptors
– Overexpression provides
basis for regulation by
SST
– SST receptor activation
inhibits secretory and
proliferative activity
35
Pathophysiology
Significance of Somatostatin Signaling

36. Octreotide May Have a Direct
Antitumour Effect via sst2 and sst5
sst5
↑ Apoptosis ↓ Cell growth
PI3K
PDK1
Akt
GSK3β
p53
↑Zac1
mTOR
p70S6K
sst2
JNK
G protein
SHP1
NF-KB
sst2
G protein
G protein
SHP1
SHP2
Src
PTPŋ
MAPK
p27
cGMP↓
PKG↓
• sst2 and sst5 both
downregulate MAPK
• sst2 binding effects the
P13K/Akt/mTOR
pathway and SHP1
signalling
• Antiproliferative effect
also mediated via
protein tyrosine
phosphatase (PTPase)
modulation
Florio T et al. Front Biosci 2008;13:822–840
Grozinsky-Glasberg S et al. Neuroendocrinology 2008;87:168–181
Theodoropoulou M et al. Cancer Res 2006;66:1576–1582

37. • Phase III randomized, double-blind, placebo-controlled study
• Primary endpoint: Time to tumour progression (blinded central review)
• Secondary endpoints: objective response rate, survival, quality of life, safety
PROMID: Evaluation of the Antiproliferative
Effect of Octreotide LAR 30 mg
Patients with midgut NETs
• Treatment naïve
• Histologically confirmed
• Locally inoperable
or metastatic
• Well differentiated
• Measurable (CT/MRI)
• Functioning or non-
functioning
Octreotide LAR
30 mg im
every 28 days
Placebo im
every 28 days
RANDOMIZATION(1:1)
Treatment until
CT/MRI
documented
tumour
progression or
death
Month 3 6 9 12 15 18
Rinke A et al. J Clin Oncol 2009;27:4656–4663

38. Patient Demographics
Octreotide LAR
30 mg (n=42)
Placebo
(n=43)
Total
(n=85)
Median age, years (range) 63.5 (38–79) 61.0 (39–82) 62.0 (38–82)
Sex male (%)
female (%)
47.6
52.4
53.5
46.5
50.6
49.4
Time since diagnosis, months (range) 7.5 (0.8–271.2) 3.3 (0.8–109.4) 4.3 (0.8–271.2)
Karnofsky score ≤80 (%)
>80 (%)
16.7
83.3
11.6
88.4
14.1
85.9
Carcinoid syndrome* (%) 40.5 37.2 38.8
Resection of primary (%) 69.1 62.8 65.9
Hepatic tumour load
0%
0–10%
10–25%
25–50%
50%
16.7
59.5
7.1
11.9
4.8
11.6
62.8
4.7
9.3
11.6
14.1
61.2
5.9
10.6
8.2
Octreoscan positive (%) 76.2 72.1 74.1
Ki-67 up to 2% (%) 97.6 93.0 95.3
CgA elevated (%) 61.9 69.8 65.9
* not requiring octreotide for symptom control
Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.
PROMID

39. Octreotide LAR 30 mg Extends TTP in Patients with Functioning and
Non-functioning Tumours
0
0.25
0.5
0.75
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
0
0.25
0.5
0.75
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
Based on the per protocol analysis
P=0.0008; HR=0.25 [95% CI: 0.10–0.59]
Proportionwithoutprogression
P=0.0007; HR=0.23 [95% CI: 0.09–0.57]
Proportionwithoutprogression
Patients with non-functioning tumours Patients with functioning tumours
Time (months)Time (months)
Octreotide LAR 30 mg: 17 pts / 11 events
Median TTP 14.26 months
Placebo: 16 patients / 14 events
Median TTP 5.45 months
Octreotide LAR 30 mg: 25 pts / 9 events
Median TTP 28.8 months
Placebo: 27 patients / 24 events
Median TTP 5.91 months
Arnold R. Abst #4508 presented at ASCO 2009, Orlando FL
Rinke A et al. J Clin Oncol 2009;27:4656–4663

40. • Everolimus
– Loss of TSC2 and NF1 are both associated with
mTOR activation
– mTOR pathway mutations were also found in
sporadic pNETs
– RADIANT-1
• 160 patients were treated in two strata, with
everolimus (n = 115) or everolimus plus octreotide (n =
45) based on whether patients were on octreotide at
study entry
• Advanced pNETs with progression following
chemotherapy
• Median PFS for patients receiving everolimus or
everolimus plus octreotide were 9.7 months and 16.7
months, respectively

41. – RADIANT- 3
• 410 patients with progressive pNETs were randomly
assigned to receive everolimus or placebo
• Everolimus prolonged median PFS from 4.6 months to
11 months leading to a 65% risk reduction for
progression compared to placebo (HR = 0.35; 95% CI,
0.27 to 0.45; p <0.0001).
• Treatment also reduced the level of tumor-secreted
hormones

42. • Sunitinib
– Activity against VEGF receptors, c-Kit, and platelet-
derived growth factor receptor
– 3 study compared sunitinib to placebo in pNETs
– Results of an early unplanned analysis showed
improved PFS (5.5 months versus 11.4 months).
– Due to the small number of events and unplanned
nature of the analyses, the results failed to cross
the O’Brian Fleming efficacy threshold for
statistical significance

44. Cytotoxic Chemotherapy
• Role of cytotoxic chemotherapy continues to
be debated
• Streptozocin-Based Chemotherapy
– Streptozocin was originally isolated from
streptomyces achromogenes in the 1950s
– Antitumor activity in pNETs was first reported in
1973; in a study that included 52 patients, a
response rate of 50% was reported

45. – Eastern Cooperative Oncology Group
subsequently compared this combination to
streptozocin plus doxorubicin72 and reported a
significantly higher response rate (69% versus
45%), time to progression (median, 20 months
versus 7 months), and OS (median, 2.2 years
versus 1.4 years) for streptozocin plus doxorubicin
than for streptozocin plus 5-FU.
– Based on these data, combination chemotherapy
with streptozocin-based regimens is considered
the standard treatment option by many

46. – Two small retrospective series have recently cast
doubt on the value of streptozocin-based
chemotherapy.
– Each of these studies examined only 16 patients.
– Both reported a disappointing radiologic response
rate of only 6%

47. • Dacarbazine- and Temozolomide-Based
Chemotherapy
– Dacarbazine was initially studied in a phase 2 study
that included 42 patients with pNETs. A response rate
of 33% was observed
– Temozolomide-based therapy is generally well
tolerated, absolute lymphopenia may occur and has
been associated with opportunistic infections.
– These studies suggest that temozolomide may have
activity in pNETs.
– A randomized study comparing temozolomide versus
temozolomide plus capecitabine is ongoing

48. • Peptide Receptor Radiotherapy
– 111In-, 90Y-, or 177Lu-labeled somatostatin analogues
have reported promising results in the control of
hormone-associated symptoms
– Largest reported series, a response rate of 30% was
found among a subset of 310 patients.
– However, if intent-to-treat analysis were performed,
the objective response would be approximately 18%
– Toxicities with peptide receptor radiotherapy included
nausea, vomiting, abdominal pain, cytopenia, and hair
loss.
– More serious side effects, including renal failure,
leukemia, and myelodysplastic syndrome, have also
been reported
– Large-scale random assignment trials are needed to
define its role in the management of pNETs.s

49. Liver-Directed Regional Therapy
• Liver is the most common and sometimes the
only site of metastasis
• Treatment approaches are generally palliative
• In the absence of a hormonal syndrome,
typical indications for liver-directed therapy
– Right upper quadrant pain,
– Early satiety due to gastric compression by an
enlarged left hepatic lobe, and the need to
– Control slowly progressive but bulky disease

50. • Hepatic Artery Embolization and
Chemoembolization
• Liver has dual blood supply, the normal liver
derives most of its blood supply from the portal
circulation
• pNET metastases, however, receive most of their
blood supply from the hepatic artery
• Interruption of the blood supply from the hepatic
artery preferentially causes ischemic necrosis of
the metastases while sparing most of the normal
liver

51. • The choice of embolic material varies by
center and may include lipiodol or ethiodized
oil, small plastic particles, or gelatin foam
particles
• Chemoembolization, cytotoxic agents are
administered intra-arterially before the vessels
are embolized, as this approach has the
potential to enable delivery of a higher
chemotherapy dose to liver metastases

52. • Retrospective study from MD Anderson, where the
outcome of patients with pNET were separately
examined, the objective tumor response rate was 35%
• Bland embolization group was compared with the
chemoembolization group, a trend was observed for
improved response rate with the addition of
chemotherapy (50% versus 25%; p = 0.06)
• Investigators compared doxorubicin with streptozocin
during embolization and reported a higher response
rate with streptozocin-based chemoembolization after
multivariate analyses

53. • Constellation of transient symptoms and laboratory
abnormalities, sometimes referred to as
“postembolization syndrome,” occurs in most patients
• Abdominal pain, nausea, fever, fatigue, and elevated
liver enzymes
• Crises related to massive release of hormone(s) may
occur in the presence of functional tumors;
prophylactic administration of somatostatin analogues
should always be considered
• To minimize the risk of hepatic insufficiency,
embolization should be carried out in one liver lobe at
a time
• In patients with bulky disease or poor liver function,
more limited embolization of liver segments should be
considered

54. • Radioactive microsphere embolization is
emerging as a well-tolerated outpatient
procedure providing symptom relief and
varying response rates
• Prospective studies are lacking in patients
with NETs and specifically those with pNETs

55. Hepatic Metastasectomy and
Transplantation
• Aggressive surgical resection has a role in the
management of metastatic islet cell carcinoma
• Series of 170 patients with NET at Mayo Clinic
– Total of 52 pNETs were included in this study
– OS rate for all 170 patients was reported to be
61% and 35% at 5 and 10 years, respectively
– Liver resection is not curative in most patients; the
disease recurrence rate was 85% at 5 years

56. • Patients with more extensive but still
resectable disease, we advocate resection for
those tumors with favorable biologic
characteristics
• Liver resection should be avoided in patients
with a high-grade histologic subtype
• Hepatic transplantation for the management
of pNETs should be considered investigational

57. • Radiofrequency Ablation
• RFA can be carried out during laparoscopy,
laparotomy, or via a percutaneous approach

58. • Choosing therapy at each stage should take
into account the aggressiveness of the tumor,
the burden (volume) of disease, and any
symptoms due to tumor burden or hormonal
secretion

64. Functional Tumors
• Gastrinoma, or Zollinger-Ellison syndrome (ZES)
– Rare disease caused by a NET (gastrinoma) in the pancreas
or duodenum
– Hypersecretion of gastrin results in uncontrolled
stimulation of parietal cells and production of gastric acid
causing refractory peptic ulcer disease
– If the serum gastrin level is still elevated 1 week after the
patient has stopped acid-suppressive therapy, it is then
important to measure gastric pH
– Patients with ZES should have a gastric pH of <2
– Serum gastrin ≥1,000 pg/ml or 10-fold above the normal
range, and a gastric pH ≤2 secures the diagnosis of ZES

65. ZES contd.

66. ZES contd.
• Clinical Features
– Abdominal Pain 70%
– Diarrhea 70%
– Heartburn 50%
– Nausea 25%
– Vomiting 20%
– Weight Loss 15%

67. – Patients with gastrin levels between 100 pg/ml
and 1,000 pg/ml and a gastric pH ≤2, a secretin or
calcium stimulation test should be considered
• Positive secretin test is associated with a postinjection
serum gastrin level increase of >200 pg/ml
• Positive calcium stimulation test with a postinjection
serum gastrin level increase of >395 pg/ml
– Duodenal location being the most common
– In pancreas -pancreatic head or uncinate process
– Serum gastrin levels correlate with the extent of
disease

68. – Tumor localization studies should be performed as part of
the preoperative evaluation
– Upper endoscopy with EUS of the pancreatic head and
duodenum, multidetector CT, and somatostatin receptor
scintingraphy
– When all localization studies are negative, the gastrinoma
is most likely in the duodenum, which must be opened
surgically (duodenotomy) to successfully locate and
remove the tumor
– For pancreatic gastrinomas, the operation is based on the
anatomy of the tumor and may consist of enucleation or
pancreaticoduodenectomy
– Regional lymphadenectomy is critically important.

69. • Management of Advanced Gastrinoma
– The introduction of PPIs brought significant advances in
the management of ZES, allowing for once or twice daily
dosing
– Dose of PPIs required to manage ZES is significantly higher
than typically used in idiopathic peptic ulcer disease
– Advanced gastrinoma is the development of type II gastric
carcinoids in the setting of MEN1-associated ZES
– Gastric carcinoids are often small, multifocal, and of low
malignant potential
– When few in number, they can often be excised
endoscopically

71. Insulinoma
• Most common functioning pNETs - 60% of functional
tumours
• Seldom malignant
• 10% of insulinomas are multiple, 10% malignant, and 10%
are associated with the Multiple Endocrine Neoplasm
(MEN) type 1 syndrome
• Insulinoma may occur either as a unifocal sporadic event or
as part of MEN1
• Uncontrolled secretion of insulin results in hyperglycemia,
manifested by neuroglycopenic symptoms such as blurred
vision, confusion, and abnormal behavior, which may
progress to loss of consciousness and seizure
• occur anywhere throughout the pancreas

72. • Body releases catecholamines, which elicit perspiration, anxiety,
palpitations, and hunger
• Weight gain
• Supervised fasting of the patient, including laboratory evaluation
and clinical observation
• Serum levels of plasma glucose, C-peptide, proinsulin, insulin, and
sulfonylurea are measured at intervals of 6 to 8 hours and
• When symptoms develop
– Insulin level >3 μIU/ml (usually >6 μIU/ml) when their blood glucose is
<40 to 45 mg/dL.
– The insulin-to-glucose ratio is ≥0.3 reflecting the inappropriate
secretion of insulin at the time of hypoglycemia
– Increase C peptide levels

73. • Localization studies performed as part of the
preoperative evaluation include
– Contrast-enhanced, multidetector CT
– Upper endoscopy with EUS of the pancreas
• Tumor localization is not successful
– Regionalization of an insulinoma is performed with
selective arterial calcium stimulation and hepatic vein
sampling
• Elevation of hepatic vein insulin following calcium
infusion of the gastroduodenal artery and/or SMA -
head or uncinate process
• The splenic artery - body or tail of the pancreas

74. • Standard treatment is enucleation
• Segmental resection of the pancreas, distal
pancreatectomy, or pancreatico
duodenectomy may be necessary
• Large defects in the pancreas resulting from
enucleation are usually treated with a Roux-
en-Y pancreaticojejunostomy to prevent a
pancreatic leak at the enucleation site

75. • Management of Advanced Insulinoma
– Glycemic control is a key aspect of managing malignant
insulinomas
– Mild symptoms sometimes can be controlled by diet
– Medical therapy may include diazoxide, an
antihypertensive agent known to increase blood sugar
– Glucagon may also have a role in the management of
insulinomas
– Short-acting somatostatin analogues be initiated under
direct medical supervision
– The efficacy of everolimus for the treatment of insulinoma
has been confirmed in several case series
– Streptozocin-based chemotherapy

77. VIPoma
• Cause of the classic Verner-Morrison syndrome
• Vasoactive intestinal peptide, which can cause watery
diarrhea, hypokalemia, and achlorhydria
• Patients can have more than 20 bowel movements a
day, with a daily stool volume exceeding 3 L
• In adults arise from the pancreas.
• In children extrapancreatic location
• Control of diarrhea is an important part of
management
• Somatostatin analogues108; octreotide can promptly
control diarrhea in 80% to 90% of patients
• Interferon is rarely used in the frontline setting, but it
may have a role in cases refractory to somatostatin
analogues
• Cytoreduction should be initiated whenever possible.

78. • 0.05-0.2 new cases per million adults
• Third most common neuroendocrine tumor of the
pancreas
• Solitary, found in body or tail.
• 2/3 malignant
• Male-to-female ratio in children - 1:1,
in adults. - 1:3

79. • Constant features
– Watery Diarrhea
– Hypovolemia
– Hypokalemia
– Acidosis
• Variable features
– Achlorhydria or hypochlorhydria
– Hypercalcemia
– Hyperglycemia
– Flushing with rash.

80. • Diagnostic triad
– Secretory diarrhea
– High levels of circulating VIP > 150pg/ml
– A pancreatic tumor
• Localization
– SRS - 91% of primary tumors and 75% of metastases.
Nikou GC, et al. Hepatogastroenterology 2005
– Endoscopic ultrasound.
– CT
– MRI
– Arteriography
– IOUS

81. • Management
 Correction of metabolic abnormality
Octreotide
Distal pancreatectomy/Debulking
VIPoma contd.

82. • Glucagonoma
– Diabetes and a characteristic rash known as
necrolytic migratory erythema
– Weight loss, diarrhea, glossitis, and angular
stomatitis have also been reported
– Somatostatin analogues may have a role in the
management of the hormonal syndrome in
patients with unresectable tumors
– Oral hypoglycemic agents and insulin can be used
to control the diabetes

84. Somatostatinoma
• Arise from the pancreas or the duodenum
• Insidious and nonspecific nature of the symptoms
- diagnosed at an advanced stage
• Diabetes, diarrhea, and jaundice due to biliary
obstruction
• Associated with von Recklinghausen disease
(neurofibromatosis)
• Management for somatostatinomas parallel
those of nonfunctional pNETs

85. Adrenocorticotropic-Secreting Tumors
• Cushing syndrome due to ectopic production
of adrenocorticotropic hormone.
• Metyrapone, ketoconazole, and mitotane tend
to be more effective

86. High-Grade Neuroendocrine Carcinoma
• Early systemic dissemination and rapid growth
• Clinical behavior with small-cell carcinomas of
the lung
• Induction chemotherapy even for localized
potentially resectable cases due to the
aggressive nature of this disease and the high
rate of relapse