2. Introduction
• Diverse group of neoplasms arising from cells
in the diffuse neuroendocrine system
• Develop anywhere in the body
• Most commonly seen in:
GI Tract- 40-45%
Lungs- 20-25%
Pancreas- 17-20%
• Primary site cannot be found in 15% of cases
3. • The term GEP-NETs is currently the adopted
nomenclature for all the NETs of the GI tract
and pancreas
• Rudolf Heidenhain discovered neuroendocrine
cells in 1870
• The first report of a PNET was done by Albert
Nicholls in 1902
• Islet cell tumors/ APUDomas/ Kulchitsky cell
tumors/ Argentaffinomas
4. • PNETs are capable of hormone production and
may be functional
• Do not secrete hormones/ secrete them in
minimal quantities/ or secrete peptides that
do not result in an obvious syndrome are non
functional
• 45%-60% are non-functional, and 40%-55%
are functional
• >50% are metastatic at diagnosis
5. Epidemiology
• Incidence of GEP-NETs over the last 5 years is
3.65 / 100,000 (according to the SEER
database, USA )
• Males> Females
• 10 to 20% are associated with inherited
syndromes like MEN1, VHL, NF1
6. Endocrine pancreas
• Islets of Langerhans
• One million in normal adult pancreas
• Each islet contains 3000 cells
• They constitute 1-2% of pancreas volume
while 10-15% of its blood flow
• Larger islets located around major arterioles
• Smaller ones embedded deep in parenchyma
• Originate from neural crest cells –APUD cells
7. Distribution and functions of islet
cells in pancreas
Cell Type Hormone Produced Endocrine
Tumor/Syndrome
Distribution of Cells
Throughout the
Pancreas
Alpha (A) Glucagon Glucagonoma Uniform throughout
Beta (B) Insulin Insulinoma Body/Tail
Delta (D) Somatostatin Somatostatinoma Uniform throughout
F PP PPoma Uncinate process
D2 VIP VIPoma/WDHA Uniform throughout
G Gastrin Gastrinoma/ZES Not present in normal
state
8. Pathology in PNETs
• Origin: Previously thought to arise from islets
cells of pancreas
• Now understood to originate from
multipotent stem cells in duct that give rise to
all epithelial cell types in the pancreas and GI
tract
9. • Benign and malignant NETs appear
histologically similar as uniform, clustered
nests of normal islet cells
• Malignancy is defined by presence of local
invasion or metastasis to distant sites
• Metastasizes to liver, lymph nodes, lung, bone
and peritoneum
10. Types
Non-functional
(Detected incidentally or due
to symptoms produced by
mass effect)
Functional
(Detected early due to
symptoms produced due to
hormone excess)
• Insulinoma
• Gastrinoma
• VIPoma
• Glucagonoma
• Somatostatinoma
11. Imaging Modalities
• Done to establish diagnosis as well as for
localization of tumor
• CT is most commonly used
Multiphase
Thin slices (3 mm or less)
Contrast enhanced
100-150 ml IV contrast(Iodixanol)
Oral neutral contrast (water)
12. • Enhancement in early
arterial phase prior to
pancreatic
parenchymal
enhancement
• Sensitivity is 82% and
related to size of tumor
A. Arterial phase CT showing a well-
circumscribed, enhancing PNET
(arrow)
13. • MRI:
Sensitivity of 79%
PNETs show low signal-intensity on T1 while high
on T2
More sensitive than CT for liver metastasis
So preferred in patients in which hepatic
debulking is planned
• Endoscopic Ultrasound (EUS):
Detection of small lesions (<1 cm) with 80%
FNA can also be done
14. Somatostatin-receptor Scintigraphy
(SRS)
• PNETs overexpress somatostatin-receptor
(SSTR) subtype 2 (except insulinomas)
• Radiolabeled somatostatin analogue (111In-
DTPA-D-Pheloctreotide)
• Sensitivity of 80% (except Insulinomas)
• Also detects hepatic metastasis
• Does not show exact location of tumor
15. Other modalities
• 18-FDG PET scan: Poorly differentiated NET
• Angiography: Small insulinomas
• Arterial stimulation venous sampling (ASVS):
Inject Calcium or secretin into celiac and superior
mesenteric arteries
Simultaneous portal venous sampling for
hormones
Sensitivity over 90%
Invasive and obsolete
16. Role of Tumor markers and IHC
• Serum markers:
Chromogranin A (CgA):
Raised in both functional and NF-PNETs
Predicts disease burden and poor prognosis
Used for follow-up
PPI should be stopped 2 weeks before measurement
Pancreastatin
Pancreatic polypeptide
Neuron-specific Enolase (NSE)
17. • Immunohistochemistry (IHC):
Chromogranin A (CgA):
Synaptophysin
CD-56
NSE
Cytokeratin
Hormones produced by functional PNETs: Insulin,
gastrin, glucagon, VIP and somatostatin
18. Grading and Classification
• Grading done by Ki-67 index (proliferative
index) and mitotic rate- WHO 2017
• Staging done on the basis of AJCC 8th edition
21. Non-functional PNETs
• Endocrine origin with no definable hormonal
syndrome
• PP, Neurotensin, and Calcitonin-secreting
tumors are also classified as nonfunctional
• Discovered incidentally or
• May produce non-specific symptoms due to
tumor mass effects
22. • Diagnosed in 4th or 5th decade
• 60-80% have metastasized to distant organ at
time of diagnosis
• Diagnosis made by:
Biopsy from tumor or liver metastasis
Tumor markers (CgA, NSE and Pancreastatin)
• Localization of tumor done
23. • Treatment Protocols (as per ENETS 2016)
Asymptomatic, small, less than 2 cm and grade I/II
tumors kept on surveillance
Tumors at head of pancreas
High surgical risk patients
• Indications for surgery :
Change in tumor size
Development of symptoms
24. • Enucleation inadequate- Invasiveness
• Partial pancreatic resection done
• For advanced PNETs extended surgical
resection done
• Simultaneous surgical resection of liver
metastases and primary tumor to be done
• Except pancreaticoduodenectomy with major
hepatectomy
25. Functional PNETs:
1) Insulinoma
• Most common F-PNETs
• Incidence- 1 per 10,00,000
• No gender or race predilection
• Mean age at diagnosis- 45 years
• 90% are benign
• Typically small: average size of 1.0–1.5 cm.
26. • 3% located in duodenum, splenic hilum or
gastrocolic ligament
• Excess Proinsulin produced
• Symptoms: due to sympathetic response to
hypoglycemia
Headache, lethargy, dizziness
Diplopia, palpitation, anxiety
Hunger and weight gain
Occur at early morning or after exercise
27. • Whipple’s Triad:
Low glucose level (<50 mg/dL)
Symptoms of hypoglycemia which causes
neurological, psychiatric and autonomic
symptoms
Which resolve with administration of glucose
• For diagnosis 72 hours fast test gold standard
Documented blood glucose level <50 mg/dL
Concomitant insulin levels >6 mU/mL
Elevated C-peptide levels (> 200 pmol/L)
Absence of sulphonylurea in plasma
29. • Treatment:
Preoperative Diazoxide: 3 mg/kg/d two to three
divided doses- Hypoglycemia prevention
Surgical resection is usually curative
Enucleation is preferred (except where tumor is
within 2 mm of main pancreatic duct[MPD])
Laparoscopy is preferred
If tumor abuts MPD- distal/ Central
pancreatectomy, pancreaticoduodenectomy done
30. • In multifocal disease or MEN1- combination of
partial pancreatic resection and enucleation
• Total pancreatectomy not indicated
• Metastatic disease:
If resectable then resection with octreotide and
chemotherapy
If unresectable then palliative treatment
• Percutaneous or EUS guided ablation in
patients unwilling or unfit for surgery
31. 2) Gastrinoma
• 2nd most common F-PNET
• Incidence-1 per 2.5 million
• Mean age at diagnosis- 50 years
• Male predominance (60%)
• >60% are malignant and multifocal, and have
lymph node and liver metastasis
• 20-30% associated with MEN1
32. • 0.2-2% patients of PUD have ZES
• Excess uninhibited Gastrin production
• Symptoms:
Abdominal pain
Heartburn
Diarrhoea secondary to acid hyper secretion
which is relieved by nasogastric suction
Weight loss
Melena and perforation may occur
33. • Diagnosis: challenging
Fasting Gastrin level
100-1000 pg/mL &
Gastric pH> 2
>1000 pg/mL &
Gastric pH< 2
Gastrinoma
Gastrinoma
Basal acid output>15 mEq/h &
Secretin stimulation test
Rise in S. Gastrin by > 110-200 pg/mL
36. • Treatment:
Sporadic Gastrinoma- Complete surgical resection
with lymph node dissection
Small, well encapsulated tumors within pancreas-
Enucleation
Large, unencapsulated tumors deep within
pancreas- Segmental resection (Distal
pancreatectomy or pancreaticoduodenectomy)
In patients with MEN1- Pancreaticoduodenectomy
Metastatic- Palliative cytoreduction
37. 3) VIPomas
• Rare with incidence- 1 per 10 million
• Bimodal age distribution: most at middle age
• Approx. 10% before the age of 10
• Over 70% patients have metastatic disease at
the time of presentation
• Solitary, large and are usually diagnosed at >3
cm in size
• 10% associated with MEN1
38. • Excess of Vasoactive intestinal peptide
• Causes Verner-Morrison syndrome also known
as WDHA syndrome (Watery Diarrhea,
Hypokalemia, and Achlorhydria) or pancreatic
cholera
• Symptoms:
Watery diarrhoea independent of food intake
Weight loss
Crampy abdominal pain
39. • Electrolyte imbalance and metabolic acidosis
• Hypokalemia is profound- sudden death
• Diagnosis: straight forward
Fasting serum levels of VIP >200 pg/mL
• Localization: CECT sufficient- large size and
distal pancreatic location
40. • Treatment:
Aggressive preoperative hydration
Correction of electrolyte abnormalities and acid-
base disturbances
Octreotide used preoperatively to reduce diarrhea
volume
Surgical resection is the treatment of choice
Metastasis: Debulking in combination with
somatostatin analogues (SSA)
Streptozotocin based chemotherapy (with 5-FU)
may be used
41. 4) Glucagonomas
• Exceedingly rare-incidence of 1 per 20 million
• 2-3 times more common in women
• Larger than most other pancreatic endocrine
tumors
• Almost always found within pancreas
• 60-70% are malignant
• Sporadic and rarely associated with MEN1
42. • Characterized by Four D’s:
Diabetes mellitus-Type 2
Deep vein thrombosis
Depression
Dermatitis (necrolytic
migratory erythrema) on
trunk and extremities
• Severe catabolic state
43. • Hypoaminoacidemia and normochromic
normocytic anemia are also common
• Diagnosis:
Fasting serum glucagon levels >1,000 pg/mL are
diagnostic
• Localization:
Most tumors are large, usually more than 4 cm
and easily localized with a CECT
44. • Treatment:
Supplemental enteral nutrition with high doses of
octreotide
DVT Prophylaxis
Total Parenteral Nutrition
Dacarbazine is effective against glucagonoma as
compared to other PNETs
Surgical resection
Metastasis: Debulking with SSA
45. 5) Somatostatinomas
• Most uncommon and rarest- <1% of all F-PNETs
• Large and solitary
• In fifth or sixth decade
• Over 60% found in the pancreas (usually the
head)
• Also found in the duodenum and small intestine
• Metastases to the liver or lymph nodes
commonly noted at the time of diagnosis.
47. • Treatment:
Surgical resection is the treatment of choice
High frequency of malignancy mandates
pancreaticoduodenectomy and pancreatectomy
Metastasis: Debulking with octreotide and
interferon-alpha may improve symptoms
48. Grade3 PNETs and NEC
• Neuroendocrine carcinomas (NEC) are rare in
the gastrointestinal (GI) tract
• Frequent in the form of small cell carcinoma
(SCLC) in the lung
• NEC show a genetic profile different from NET
with frequent mutations in p53 and RB
• A lung primary should be excluded before any
intervention
49.
50.
51. Management of Metastatic disease
• At initial diagnosis >40–50% of PNETs patients
present with distant metastases
• MC site- Liver (80%)
• Metastases to the bone, distant lymph nodes,
and peritoneal cavity also frequent
• Liver failure is the most common cause of
death
• Cytoreductive surgery as a standard treatment
52.
53. Liver transplantation
• Resection of the primary before
transplantation produces better results than
simultaneous resection
• Criteria:
Well differentiated tumor
Less than 50% of liver involvement
No extrahepatic metastasis
Those with prolonged disease stability in which
favourable prognosis is expected
54. Role of Systemic Therapy
• Somatostatin analogue (SSA), octreotide and
lanreotide, are effective drugs for syndrome
control in functional NETs (CLARINET trial)
• SSA are recommended as a first-line therapy
in pancreatic NET (up to a Ki-67 of 10%)
55. • IFN-alpha used as second-line (add-on)
therapy in refractory carcinoid syndrome or
functional pancreatic NET
• Everolimus (mTOR inhibitor) or Sunitinib
(Tyrosine kinase inhibitor) are generally
recommended after failure of SSA or
chemotherapy in pancreatic NET (RADIANT-4)
56. Chemotherapy
• STZ-based chemotherapy is one of the
treatment options in pancreatic G1/G2 NET
next to SSA and novel targeted drugs
• In G3 NET capecitabine and temozolomide
(CAPTEM) regimen may be considered
• In G3 NEC, platinum-based chemotherapy is
recommended as a first line therapy
57. Peptide receptor radionuclide therapy
(PRRT)
• Recommended after failure of medical
therapy
• Therapeutic option in progressive SSTR-
positive NET with homogenous SSTR
expression
• Radioligands used are 90Y-DOTA-Tyr3-
octreotide (90Y-DOTATOC) and 177Lu-DOTA-
Tyr3-octreotate (177Lu-DOTATATE)-NETTER-1
58. Prognosis
• Liver metastasis is most important factor
• Other factors are:
Presence of calcification at preoperative imaging
Distant metastases and their progression time
Lymph node involvement
Absence of symptoms in NF-PNETs has better
prognosis
Peritumoral vascular invasion
Old age >55 years- high mortality
59. Follow-up
• Regular follow-up with cross-sectional imaging,
scintigraphy, CgA done
• G1 PNETs: 6 monthly
• G2 PNETs: 3 monthly for first 2 postoperative
years and at 6 months thereafter
• Advanced and metastatic PNETs with stable
tumors 6 months
• PNETs undergoing chemotherapy, molecular
targeted therapy or PRRT : 3 months
