The document discusses neuroendocrine tumours (NETs), including their epidemiology, histology, classification, molecular pathogenesis, syndromes associated with NETs, and details specific neuroendocrine tumours like insulinomas, gastrinomas, their diagnosis and treatment. NETs originate from neuroendocrine cells in the gastrointestinal tract and other organs and can secrete hormones. Diagnosis and treatment of functional NETs depends on identifying the syndrome caused by hormone secretion and controlling the clinical effects.

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