pancreatic neuroendocrine tumors

1. NEUROENDOCRINE
TUMOURS
PART - 1
Shankar Zanwar

2.  CarcinOIDs – for less aggressive tumours than
adenocarcinomas – Oberndorfer(1888)
 Neuroendocrine tumours in gastrointestinal tracts
–
 Pancreatic neuroendocrine tumours
 GI carcinoids
 Pancreatic neuroendocrine tumours
 Functional – with clinical syndrome
 Non – functional – without it

3. Epidemiology
 Annual incidence – GI NETS -7-13/106
 pNETs account for 1-10% of all pancreatic
tumours
 Peak age of incidence 6th and 7th decade
 Overall prevalence 1/105, of functional pNETs
 Non functional pNETs – 60-80% of all pNETs
Yao JC, Ann Sur Onc 2007

4. Origin of NETs
 NETs originate from diffuse neuroendocrine
cells - scattered throughout the GIT,
respiratory tract, thyroid
 Share chemical properties of Amine Precursor
Uptake and Decarboxylation –
APUDoma(earlier)
 Proposed to have common embryologic origin
in neural crest and endocrine cells
Grande, Cancer Rev 2012

5. Histology
 All NETs in common have
 Solid, trabecular, gyriform or glandular pattern.
 Homogenous sheets of small round nucleus
 Uniform nuclei, salt and pepper chromatin
 Finely granular cytoplasm
 Mitotic figures are characteristically rare <2/HPF
 Malignancy of the tumour is defined only by invasion or
mets

6.  Both GI and pancreatic NETs secrete can
produce a number of hormones – can be
identified by IHC
 Like insulin, glucagon, VIP, serotonin,
chromogranins, and HCG(α and ß sub units)
 But they seldom secrete them producing any
syndrome.

7.  All tumours of all site can secrete all hormones in the
NETs spectrum, thus localization based on hormone
using IHC for primary is difficult.
 IHC can be of help in identifying the O-methyl guanine
methyl transferases(MGMT) – DNA repair enzyme –
predicts response of temozolomide
 Half of the P-NETs are deficient in MGMT while none
of the GI-NETs  response rate of temozolomide 
34% in P-NETs while 2% in GI-NETs
Kulke Clin Cancer Res 2009

8. Classification
 Based on functionality – i.e. syndrome produced –
 Insulinoma
 Gastrinoma
 VIPoma
 Glucagonoma
 Somatosatinoma
 Growth hormone relasing factor (GRFoma)
 ACTHoma
 Rare tumours secreting – renin, erythropoietin,
leutinizing hormone and cholecystokinin.

9. Newer WHO classification
 Ki – 67
 protein product of gene – Ki 67, on chr. 10
 A/w cell replication and ribosomal RNA transcription
 Marker of cell replication
 Ki derived from the city of discovery – Kiel,
Germany.
Grade Ki 67 index Mitotic
count( per
HPF)
Differentiation
Low grade (ENET G1) <3% < 2 Well
Intermediate grade (ENET
G2)
3-20% 2-20 Well
High grade (ENET G3) >20% >20 Poor

11. Molecular pathogenesis
 Major players – Retinoblastoma and p53 gene
inactivation
 Most common altered gene in non familial
pNETs – MEN – 1 – 44%
 Other pathways – DAXX – death domain
associated protein
 ATRX – α thalassemia/mental retardation/ X
linked
 mTOR pathway – mediated through tyrosine
kinase – 15%

12. Syndromes a/w NETS
 MEN – 1 – Wermer’s synd, Chr. 11, autosomal dominant,
MEN II no NETs, characterised by
 Hypercalcemia
 Hyper parathyroidism
 Pheocromocytoma
 Without medullary carcinoma of thyroid
 Gene – Menin – transcriptional regulation of cell division
 Microscopic pNETS – 80-100%, clinical – 20-80%, GI
carcinoids – gastric – 15-35%
 Commonest pNET – PPoma – 80-100%

13.  von Hipple - Lindau synd
 Chr. 3 , autosomal dominant
 VHL gene, target hypoxia inducible factor.
 Pancreatic involvement –
 Primary cysts – 60%
 pNETs – 10-70%
 pNETs – most often asymptomatic
 Mean age 29-38
 Liver mets seen in 9-37% of pNETs pateints.

14.  Neurofibromatosis – 1
 Chr. 17, autosomal dominant
 0-10% GI carcinoid
 Most common – periampullary duodenal
somatosatinoma
 NF-1 – 48% of all duodenal SSoma, 25% of all
ampullary GI-NETs
 Tuberous sclerosis
 Autosomal dominant - hamartin gene
 pNETs seen in 4% of TSC – 56 % non functional and
44% functional
Arva NC – Am J of Surg Patho -2012

15. Insulinoma
 Always located in pancreas, non pancreatic rare
 Distributed evenly throughout pancreas
 Usually <1cm – 39%, >5cm – 8%, multiple – 3-
13%(MEN related)
 Malignancy – 5-16%; Often the larger ones (avg- 6cm)
 Well encapsulated, firmer than rest of the pancreas
and highly vascular

16.  Age – non specific, usually 20 to 75y, M:F - 2:3
 Fasting hypoglycemia
 Neuroglycopenic syndrome
 Diplopia, blurred vision commonest, others – seizures,
syncope, paresthesia weakness, least common ataxia
 Adrenergic syndrome
 Sweating, tremors
 Hunger, nausea
 Palpitations
 Patient learn to avoid fasting  eat frequently 
obesity

17. Diagnosis
 Whipple’s triad
 Traditionally – 72 hour fasting planned, and fasting insulin levels
and c-peptide measured, can stopped if any hypoglycemic event
occurs earlier
 Nearly 75-80% will develop symptoms before 24 hours.
 Plasma insulin: glucose ratio of ≥0.3 is considered diagnostic
 Most sensitive and spf. method – FBS and proinsulin
Vezzosi – Eur Jour Endocriniology - 2007
Tumour localization and metastatic disease

18. Treatment
 Diet – rapidly absorbed carbohydrates should be
avoided, slowly absorbed ones preferred –
Starches, breads, potatoes and rice
 Medical therapy
 Diazoxide
 nondiuretic thiazide – inhibits insulin release, enhances
glucogenolysis
 Initiated at 3-8mg/kg/d max upto 15mg/kg/d
 S/e – Na retention, edema, GI upset & hirsutism
 Response rate – 60%

19.  Octreotide –
 symptom control 40-60%
 Mechanism – high affinity somatostatin receptors in
tumor
 From 50 μg to 1500 μg per day
 Lanreotide newer long acting analog – 2-4 weekly
dosing
 S/e – bloating, abdominal cramps, malabsorption and
cholelithiasis
 Everolimus – For metastatic insulinoma non
responding to other therapies.
Bernard, Eur J of Endocrino
2013

20.  Surgical therapy
 When no liver mets on imaging ( >90%) – surgical
exploration enucleation/resection
 Cure rate 70-97%
 Tumour localization EUS, hepatic venous sampling after
Cal stimulation and intraop US can be used.
 Failure to localize during surgery  empirical distal
pancreatectomy only 50% success, not indicated any
more.
 Lymphnode dissection is not needed
Fendrich, Nat Rev Clincal Onco

22. Gastrinoma
 Zollinger Ellison syndrome – ectopic gastrin
secretion  excessive gastric acid secretion
 PUD, GERD and diarrhea.
 Hypergastrinemia is also seen in tumours of
 Ovary
 Lung
 Pheochromocytoma
 Acoustic neuroma
 Colorectal carcinomas

23.  Hypergastrinemia  ↑ maximal acid secretion and
basal acid output
 ↑ gastrin  parietal cell and gastric fold
hyperplasia and hyperplasia of enterochromaffin
cells  increased risk of type II gastric carcinoids
~ 23% of ZES
 ↑ acid secretion causes diarrhea
 Low pH – direct small intestinal damage
 Inactivation of lipases
 Low pH precipitates bile acids

24.  Gastrinomas - non beta islet cell tumors
 Locations of gastrinoma
 >50 % in duodenum and in duodenum
 D1 – 56%, D2- 32%, D3-6% and D4 – 4%
 Pancreas – Head:body:tail – 1:1:2
 Gastrinoma /Passaro’s triangle – 60-90%
gastrinoma location
 Non duodenal/pancreatic location – 2-24% -
ovary, liver, jejunum, omentum and pylorus

25.  Spread – lymphnode and hepatic mets
common seen in 60-90% of tumours
 Pancreatic lesion & lesions > 3cm  ↑ hepatic
mets risk
 Two growth patterns
 Aggressive – 25% - 10y survival 30%
 Non aggressive 75% - 10 y survival 96%

26.  Clinical features
 Duodenal and pancreatic gastrinoma presentation same
 M>F 3:2, avg age – 41-53y,
 Symptoms
 Pain 75%
 Diarrhea – 73%
 PUD – 71%
 Nausea, vomiting, heartburn
 Bleeds 25%, perforations 8-10%, esophageal stricture – 8-10%
Berna, medicine NIH databank 2006
 MEN – associated in 25%, possibility if
 Younger age 34y vs 43 for sporadic
 Hyperparathyroidism - h/o nephrolithiasis/ renal colic – 47%
 Personal or family history of endocrinopathies

27.  Clues to ZES
 Ulcers refractory to Rx or associated with complications
 Diarrhea with ulcers
 Non – H. pylori non NSAIDs ulcers
 Hypertrophied folds on endoscopy
 Family or personal history of endocrinopathy
 Most pts. have typical DU at diagnosis, older studies
multiple ulcers in atypical location.
 Previous studies ~100% developed complication, now
with PPI <30% present with complications

28. Diagnosis
 Diagnosis is usually delayed by 4-6 years, main cause
PPI, false +ve diagnosis may also be caused by PPi
due to hypergastrinemia
 Diagnosis of ZES needs demonstration of ↑ acid
secretion in presence of ↑ gastrin
 Thus fasting gastrin level and basal acid output
needed for diagnosis
 Fasting gastrin level ↑ in 97-99% of ZES, thus ZES unlikely
with normal gastrin level. False –ve if
 Hyperparathyroidectomy done for MEN-1

29.  PPIs can elevate fasting gastrin levels 
repeat gastrin level after 1 week of PPI
stoppage
 But rebound acidity and increased risk of
complications
 abrupt stoppage of PPI not recommended
now, use either tapering dosage or or pursue
diagnosis by other modalities - imaging

30.  Hypergastrinemia with high pH(low acidity)
 Acholrhydria – chronic atrophic gastritis, level >70X ULN
 PPI gastrin levels >4X in 25% pts
 Hypergastrinemia with low pH(high acidity)
 Gastric outlet obstruction
 Chronic kidney disease
 Short bowel syndrome
 Antral G cell hyperplasia
 These pts. secreting testing and BAO measured
 Since gastrinoma related secretin stimulation  high amount of
gastrin release (↑ secretin receptors in tumor) – gastrinemia
>120pg/ml on 2U/kg IV secretin injection
 BAO ↑ in ZES (~90%) > 15mE/hr in normal and >5mEq/hr post
surgery pts.

32. Treatment
 Two issues – Hyperacidity and gastrinoma perse
 For gastric hypersecretion
 Medical
 PPI – starting dose equivalent to 60mg omeprazole/d
 Sufficient dose is one that ↓ acid secretion <10mEq/hr before
next dose
 Upto 60mg BD may be required in severe GERD
 Since requirement of PPI may change over period – check acid
secretory control after 6 months – OGD/ BAO
 Surgical
 Earlier - total gastrectomy, Vagotomy,
 Now main surgery in ZES is parathyroidectomy - ↓ gastrin
level, ↓ BAO and ↑ sensitivity to PPI

33.  Treatment of gastrinoma perse
 Surgical exploration indicated if no
 Diffuse mets to liver
 MEN-1
 Sporadic gastrinoma – surg – 51% can be resected, 34% can have 10y
survival.
 Gastrinoma resection and routine duodenectomy reduces risk of recurrence
 Role of curative surgery in ZES related gastrinoma – controversial
 In operated pts. disease free cure rate <5% in ZES, unfavourable
because – multiple tumors in duodenum and lymphnodal spread
 Long term survival of MEN1/ZES < 2cm ~100% for 15 years
 Surgery indicated in MEN1/ZES if
 Lesion >2cm, consensus of studies only gastrinoma resection and no
pancreatoduodenctomy since adverse outcomes

35. Glucagonoma
 Syndrome caused by excess glucagon secretion
 Weight loss
 Anemia
 Glucose intolerance
 Necrolytic migratory erythema(NME)
 Most of the tumors are large 5-10cm(unlike insulinoma)
 Usually malignant
 Most common mets – liver and LN
 Most are in pancreas(90%) and most are solitary

36.  Hyperglycemia – d/t gluconeogenesis and glycolysis, glucosuria -
renal tubular damage
 Weight loss (56- 96%)– hypercatabolism, aversion to food d/t GLP-
1
 NME
 Hypoamminoacidemia
 Essential fatty acid deficiency
 ↑glucagon
 Zinc deficiency
 Anemia - ?nutritional cause not known – normocytic normochromic
 Thromboemboslism(12-35%) and psychiatric problems

37.  Clinical features
 Age 50-70
 NME (54-90%) – precedes diagnosis of glucagonoma years
before
 Starts as erythematous rash  raised bulla crustcentral
healingpigmentation(over 1-2weeks)
 Intertrigenous areas, buttocks, thighs and perineum
 Glossitis(34-68%) and angular stomatitis
 Dystrophic brittle nails
 Diarrhea(14-15%)

38.  Diagnosis
 Usually suspected d/t rash - NME
 13-17% are part of MEN-1, and 20% may be a/w ZES
 Fasting plasma glucagon level >200pg/ml usually 500-600
 Mild elevation may be seen in
 DKA
 Pancreatitis
 Cirrhosis
 Sepsis
 Acromegaly
 Hepercorticism
 Celiac, startvation

39. Treatment
 Medical
 Nutritional rehabilitation –hyperalimentation or
TPN
 Treatment of diabetes
 NME treatment nutritional replacement may treat
NME
 Long acting somatostatin – octereotide may help in
30%
 DM no help
 100-400 μg/d

41.  Surgical
 Since usually malignant surgical treatment
considered in all resectable cases
 50-90% have mets at diagnosis
 Many develop recurrences

42. VIPoma
 Vasoactive intestinal polypeptide excess secretion,
that causes syndrome of
 Watery diarrhea
 Hypokalemia
 Acholrhydria
 Also known as pancreatic diarrhea
 Most are pancreatic, 42-75% occurring in the tail
region
 Extrapancreatic –liver, retroperitoneum and
esophagus

43.  Unlike other mets in HPE if VIP is detected it is
very likely of VIPoma
 Flushing(14-33%) – vasodilatory effects of VIP
 Hypokalemia – fecal K loss
 Hypercalcemia and achlorhydria mechanisms
not know

44.  Clinical features
 Mean age 42-51y,
 Diarrhea – 89-100%
 May be episodic
 Like tea water
 ~1 liter /d, usually >3 liter
 Persist during fasting
 Most patients > times a day
 No steatorrhea
 Weight loss, abdominal cramps
 Volume depletion 44-100%
 Tetany due to hypomagnessemia

45.  Diagnosis
 Secretory diarrhea persisting on fasting gives clue
 Exclude – celiac disease, laxative abuse, HIV
 VIP levels – Normal 0-180pg/ml, Sn – 88%, Sp -100%
 Other conditions that ↑ VIP
 IBD
 fasting
 CKD
 Radiation enteritis
 Small bowel resection
 Nesidioblastosis
 In diagnostic dilemma – intestinal perfusion studies – where net
secretion of electrolytes instead of absorption is seen

46. Treatment
 Medical
 Fluid and electrolyte replacement
 May require >5L/d of fluid
 K+ replacement - ~350mEq/d
 Diarrhea – Octreotide helps in 78-100%
 22% require increase in dosage at 6 months
 Surgical
 Imaging to assess the localization and
resectability
 Surgical resection helps in 1/3rd and 30% are
cures.

48. Somatostatinoma
 Usually originate in SI and pancreas
 Syndrome of somatostatinoma
 Diabetes
 Gallbladder disease
 Diarrhea
 Weight loss
 Hypochlorhydria
 Rarest of all pNETs

49.  Just presence of somatostatin in tumor- does’nt suffice
somatostatinoma
 Majority occur in pancreas 47-75%
 Extrapancreatic are usually in duodenum(90%) and in the ampullary
region(90%)
 Often solitary, size 1.5-10cm
 Mets seen in 43-90% at the time of surgery, >2cm size 78%
sensitive for prediction of mets
 Mets more common pancreatic than duodenal

50.  Specific histologic feature of duodenal
somatostainoma – psammoma bodies – round
calcium collection
 DM is due to inhibitory action of somatostatin(SS) on
insulin
 GB disease – d/t inhibition of GB emptying by SS
 Cholelithiasis and sludge
 Hypochlorhydria – gastric acid secretion inhibition
 Weight loss – secondary to steatorrhea

51.  Clinical features
 Age 40-65
 Abdominal pain
 Weight loss
 Diarrhea – 3-10/d, steatorrhea(20-76g/d), foul smelling
 Nausea and vomiting
 Jaundice due to periampullary tumour/ stones
 A/w
 NF-1 – 7%
 MEN -1 - < 1%
 VHL

52.  Diagnosis
 Incidental
 HPE may suggest presence of SS
 Psammoma bodies may aid in diagnosis
 Modestly elevated level of SS may not clinch the
diagnosis, since ↑ only in pNETs and not so with
intestinal SSoma

53.  Treatment
 Medical –
 Correction of malnutrition – hyperalimentation or TPN
 Treatment of diabetes
 A very small number of patients may respond to somatostatin
analogs
 Surgical
 Surgically resectable 50-90%
 Late diagnosis resection is not curative
 Duodenal SSoma
 <1cm endoscopic treatment
 1-2cm transduodenal resection
 >2cm – whipples
 5 year survival – 100% without mets and with mets 33-60%

54. Nonfunctioning pNETs

55. Indian scenario
 Amrapurkar, tropical gastroenterology, 2010

58. Thank You