1. Pancreatic neuroendocrine tumors (PNETs) are rare, slow-growing neoplasms that originate from cells that produce and secrete hormones. 2. The most common functional PNETs are insulinomas, gastrinomas, glucagonomas, and VIPomas. Non-functional PNETs make up about 75% of cases. 3. Diagnosis involves biochemical testing for hormone levels, imaging such as CT, MRI, and nuclear imaging to locate the primary tumor and metastases, and pathology to determine grade and stage. Endoscopic ultrasound can help locate small tumors.

1. Pancreatic
Neuroendocrine
Tumors (Insulinoma)
DR JUNISH BAGGA
SR – GI SURGERY
GUIDE – DR SATPAL SINGH VIRK
PROF. & HEAD. GI SURGERY. DMCH

2. Introduction to NETs
 NETs arise from cells which produce and secrete hormones
 Most NETs are slow growing and malignant, with metastatic
potential
 Carcinoid, APUDomas
 Common sites of origin are:
 GI tract
 Lungs
 Pancreas
Burns WR, Edil BH (March 2012). "Neuroendocrine pancreatic tumors: guidelines for management and update". Current Treatment Options in Oncology.
13 (1): 24–34. PMID 22198808

3. Pancreatic NETs Overview
 PNETs are rare, slow-growing
neoplasms
 Symptoms from excess
hormone production or
mechanical problems
 7% of all NETs are found in
pancreas
 1-2% of all pancreatic tumors
 Historically – islet cell tumors
Amin, Mahul B., ed. (2017). "30 - Neuroendocrine Tumors of the Pancreas". AJCC Cancer Staging Manual (8 ed.). Springer. pp. 415–416. ISBN 978-3-319-
40617-6.

4. ORIGIN
 Debated
 Arise from pluripotent
stem cells in pancreatic
ductal acinar system
and not from
pancreatic islet
themselves
Schimmack S, et al: The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors, Langenbecks Arch Surg 396:273– 298, 2011.

5. Epidemiology
 Incidence rate of 0.4 cases per 100,000
 Incidence is increasing
 Males = Females
 Age – 60 – 80 years
 5% familial association – MEN1, VHL, TS, NF1
 Tend to be diagnosed at a younger age
Family history is the only identified risk factor
Fraenkel M, et al: Epidemiology of gastroenteropancreatic neuroendocrine tumours, Best Pract Res Clin Gastroenterol 26:691–703, 2012.

6. Potential Reasons for Increased
Incidence and Prevalence in PNET
• 0.17-0.43 cases / 100,000
• Exact reasons are unknown but may include:
– Potential underdiagnoses and underreporting in the past
– Improved diagnostic techniques
– Increased awareness of NET in the community
Fraenkel M, et al: Epidemiology of gastroenteropancreatic neuroendocrine tumours, Best Pract Res Clin Gastroenterol 26:691–
703, 2012.

7. Pathology
& Staging

8.  Well circumscribed solitary masses
 Majority are well differentiated
 Potential to grow & metastasise > malignant
 Likelihood of metastatic spread is very low , benign has been used as
a classification variable
 Malignant- invades locoregionally, has metastasised distantly or to
regional lymph nodes, greater than 2 cms insize, displays vascular,
lymphatic or neural invasion or has proliferative tndex of greater than
2 %
Klöppel G, et al: The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification, Ann N Y Acad Sci 1014:13–27, 2004.

9. Biologic Behaviour
GRADE AND STAGE

10. Grading system for PNETs
Good
Poor

11. Ki-67
 Antigen KI-67 also known as Ki-67
or MKI67 is a protein that in
humans is encoded by the MKI67
gene
 Ki derived from the city of
discovery – Kiel, Germany.
 Associated with cell replication
and ribosomal RNA transcription.
 Present during all active phases of
cell cycle
 Absent from resting cell – G0

12. Staging – TNM (AJCC 2010)

13. Staging

14. Classification Based on
Functional Activity
Functioning Non-functioning
PNETs may or may not have secretory symptoms
Secretory symptoms related to specific hormones
Tumors (nonfunctional) may secrete peptides but cause no
clinical symptoms

15. Non-functional PNETs
 Most PNETs ~75%
 Often found incidentally
 Symptoms relate to tumor’s mass effect – abd pain,
vomiting, weight loss, jaundice, pancreatitis
 Tend to be larger than other PNETs
 Nodes involved at time of diagnosis

16. Functional Tumors

17. Pancreatic NETs Types
Relative frequency: Asymptomatic >Insulinoma >
Gastrinoma > Glucagonoma > VIPomas >
Somatostatinoma > Others

18. Systematic Approach to
Diagnosing NET Is Needed
 History and physical exam
 Biochemical markers (serum, tissue, urine)
 Specific tests
Imaging
Computed tomography scan (CT)/ Magnetic
Resonance Imaging (MRI)
Nuclear Imaging
Endoscopic ultrasound

19. Insulinoma
 1-2% of all pancreatic tumors
 Small <2cms
 Solitary
 Rarely malignant
 5 year OS- 56%, 10 year OS -
29%
Baudin E, et al: Malignant insulinoma: recommendations for characterisation and treatment, Ann
Endocrinol (Paris) 74:523–533, 2013.
Okabayashi T, et al: Diagnosis and management of insulinoma, World
J Gastroenterol 19:829–837, 2013.

20. Diagnosis
 Whipple’s Triad
 plasma glucose- 40-50mg/dl
 Fasting induced Neuroglycopenic symptoms of
hypoglycaemia
 Resolution of symptoms after meals
 Plasma gluose, insulin,
 Proinsulin and C-Peptide over 72 hour fast
 This panel can detect 90%
Ito T, et al: Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment:
advances, Best Pract Res Clin Gastroenterol 26:737–753, 2012.

21. Gastrinoma
 1955, Zollinger and colleagues
 Sporadic- 67%, familial- 33%
 Mostly solitary
 60% malignant- spread to regional lymph nodes by time
of diagnosis
 ^ gastrin -> recurrent peptic ulcers, diarrhoea, reflux
esophagitis.
 Diagnosis-
 Thickened mucosal folds – hallmark
 Demonstration of hypergastrinemia – fasting serum gastrin
levels (10 times)
 Abnormal gasric acid secretion- gastric pH <2
 Secretin or glucagon stimulation test
Zollinger RM, et al: Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas, Ann Surg 142:709–723, 1955.
Anlauf M, et al: Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological
features, World J Gastroenterol 12:5440–5446, 2006.

22. Gastrinoma triangle
 Apex- junction of
cystic duct and CBD
 INF- 2nd and 3rd
part of duodenum
 MEDIAL- jn of head
and body of
pancreas
90% of gastrinomas lie
in this anatomic
location
Howard TJ, et al: Anatomic distribution of pancreatic endocrine tumors.
Am J Surg 159:258-264, 1990

23. Glucagonoma
 ~400 cases
 Large size >6cms
 Solitary
 Symptoms- glucose intolerance, migratory necrolytic
erythema, weight loss
 Diagnosis- elevated glucagon levels + enhancing
pancreatic mass on CT
 ~60% will have liver mets at diagnosis(Kulke et al)
 Case series of 23 gluganomas – 5 yr survival was 75%
(regardless of treatment)
Kulke MH, et al: Neuroendocrine tumors, version 1.2015: clinical practice guidelines in oncology, J Natl Compr Canc Netw 13:78–108, 2015.
Kindmark H, et al: Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years, Med Oncol 24:330–337, 2007

24. Vasoactive Intestinal Peptide
secreting neuroendocrine tumor
 Solittary, intrapancreatic tumor
 >50% malignant
 VIP – neurotransmitter & intestinal secretagogue
 “pancreatic cholera” Verner-Morrison syndrome
 Symptoms – high volume watery diarrhoea leading to
 metabolic acidosis
 Achlorhydria
 Hypokalemia
 Diagnosis – elevated plasma VIP, pancreatic tumor on
imaging
Renal failure
secondary to
hypovolemia
Verner JV, et al: Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia, Am J Med 25:374–380, 1958.
Fabian E, et al: Diarrhea caused by circulating agents, Gastroenterol Clin North Am 41:603–610, 2012.

25. Somatostatinoma
 Less defined clinical syndrome than other PNETs
 Symptoms – glucose intolerance, cholelithiasis, weight
loss, diarrhoea, steatorrhoea, anemia
 Located in the pancreas (56%) or duodenum
 Duodenal Ssomas are associated with NF-1 in 50% of
cases
 Less likely to be malignant
Nesi G, et al: Somatostatinoma: clinico-pathological features of three cases and literature reviewed, J Gastroenterol Hepatol 23:521–526, 2008.
Williamson JM, et al: Pancreatic and peripancreatic somatostatinomas, Ann R Coll Surg Engl 93:356–360, 2011.

26. Pancreatic Polypeptide- secreting
neuroendocrine tumor
 PNETs predominantly secreting PP- extremely rare
 Functional/non-functional – debated
 No specific syndrome
 Intermittent abdominal pain, pancreatitis, may develop
glucose intolerance
 MEN-1 – multifocal and malignant
 Fasting PP levels > 3 times -> presence of PNET and it
will likely be large enough to be detected on ct
Kuo SC, et al: Sporadic pancreatic polypeptide secreting tumors (PPomas) of the pancreas, World J Surg 32:1815–1822, 2008.
Mutch MG, et al: Pancreatic polypeptide is a useful plasma marker for radiographically evident pancreatic islet cell tumors in patients with multiple endocrine
neoplasia type 1, Surgery 122:1012–1020, 1997

27. Biochemical Assessment and Monitoring
for PNETS
1. Chromogranin A(CgA)- correlate with tumor burden
 CgA can be used as a marker in patients with both functional
and non-functional pancreatic endocrine tumors
 Decreses post treatment – favourable outcomes
 Rising levels may suggest recurrent or progressive disease
2. Pancreatic polypeptide- where CgA is negative
3. Pancreastatin (PST)- post translational product of CgA.
More powerful prognostic test in surgically managed PNET.
 Pts with elevated PST pre and post-op- 90% chance of
progression and 40% risk of death within 5 years.
4. Neurokinin A & Synaptophysin more diagnostic and less
prognostic.

28. Imaging and
Localisation

29. CECT
 valuable for
primary/regional/metastatic
 80-100% sensitive for tumors >
2cms
 Capturing the vascular blush in
the arterial phase is critical for
identification and differentiation
 More sensitive for liver mets
Both PNET and their metastasis tend
to be hypervascular and best seen in
arterial phase.
Arterial phase of a contrast-enhanced computed tomography of the abdomen showing an early
enhancing pancreatic neuroendocrine tumor in the head and uncinate process of the pancreas
(white arrow), with a necrotic node medially (red arrow).
Van Hoe L, Gryspeerdt S, Marchal G, et al: Helical CT for the preoperative localization of islet cell tumors of the pancreas: Value
of arterial and parenchymal phase images. AJR Am J Roentgenol 165:1437–1439, 1995.

30. Arteriographic demonstration of an insulinoma. A, Selective injection into
the specific dorsal pancreatic artery demonstrates the tumor precisely. B,
Insulinoma with triphasic enhancement on CT. The mass in the pancreatic
body (arrow) demonstrates early and prolonged enhancement
(A from Edis AJ, McIlrath DC, Ven Heerden JA, et al: Insulinoma: Current diagnosis and surgical management. Curr Prob Surg 13:1–45, 1976; B from Ros PR, Mortelé KJ:
Imaging features of pancreatic neoplasms. JBR-BTR 84:239–249, 2001.)

31. MRI
 Second line
 Superior delineation of hepatic metastasis is required
 Renal failure
Hypo intense (low signal intensity) on T1
Hyper intense (high signal intensity) on T2
In one large series of insulinomas, contrast-enhanced MRI identified
all lesions larger than 3 cm, 50% of lesions 1 to 2 cm, and no lesions
smaller than 1 cm.
Overall sensitivity for PNET 85%
Thoeni RF, Mueller-Lisse UG, Chan R, et al: Detection of small, functional islet cell tumors in the pancreas: Selection of MR imaging sequences for optimal
sensitivity. Radiology 214:483– 490, 2000.
Boukhman MP, Karam JM, Shaver J, et al: Localization of insulinomas. Arch Surg 134:818–822; discussion 822–
813, 1999.

32. Endoscopic Ultrasound
 Overall sensitivity of 93%
 High sensitivity for small
tumors less than 3cms
 More in head region
 Allows FNAC for pathologic
diagnosis
 FNAC accuracy – 90%
Muller MF, Meyenberger C, Bertschinger P, et al: Pancreatic tumors: evaluation with endoscopic US, CT, and MR imaging. Radiology 190:745–751, 1994.
Proye C, Malvaux P, Pattou F, et al: Noninvasive imaging of insulinomas and gastrinomas with endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery
124:1134–1143; discussion 1143–1134, 1998.

33. Nuclear imaging
Somatostatin receptor
scintigraphy
 Diagnosis and Surveillance
 To determine if pt will
benefit from PRRT
 SSTR 1-5
 Most common SSTR2 – well
deferentiated NET
 OctreoScan
 Radiotracer indium-111-
DPTA-octreotide
 SPECT + OctreoScan
68Ga-PETCT / DOTATOC
 Gallium-68
 DOTATOC - 68Ga-DOTA-
Tyr(3)-octreotide
 DOTANOC
 DOTATATE
 Variation in ligand affinity
for SSTR subtypes but not
clinically significant
 Superior to conventional
imaging

34. Comparison of CT, MRI , and
SRS in a patient with Zollinger-
Ellison syndrome. Neither the
CT scan (top) nor MRI (middle)
localized a gastrinoma. SRS ,
however, showed a focus in the
left lobe of the liver.

35. Intra-op usg

36. Localisation of insulinoma
 Arterial stimulation venous sampling (94-100%)
 calcium is injected successively into gastroduodenal,
proximal splenic, superior mesenteric and proper hepaic
arteries
 After each injection, venous blood is sampled from
hepatic veins at 30, 60 and 120 seconds.
 Positive localisation corresponds to 2 fold increase
hepatic vein insulin levels

37. Surgical Management
RESECTION OF THE PRIMARY TUMOR : SURGICAL
CONSIDERATIONS

38. Indications for Surgery
1. Functional, symptomatic
2. Isolated , G1 and G2 PNET greater than 2 cms
3. Patients with metastatic disease where all visible mets
can be resected
4. Palliative resection and hepatic debulking may be
considered for those pts with symptomatic advanced
disease when liver is the only focus of distant
metastasis
~80% of liver mets are resectable

39. Small, Non-functional PNET
 Serial imaging -> progression
 Lee and colleagues(2012), compared patients with non
functional PNET
 Non-operatively(77) – no change in tumor size
 Resection(56) – 9% had positive nodes (2.4cms)
 Kuo and colleagues(2013) 27.3% nodal mets and 9.1%
distant mets – reasonable number to offer patients
curative surgery
 NCDB – improved OS >5 years with resection
 2017 BJS – active surveillance of patients affected by
sporadic, small, asymptomatic NF-PNETs may…

40. Enucleation
 Limited procedure
 Low complication rates
 Better results than radical procedures in terms of blood
loss, length of surgery, less panc. Insufficiency
 Laparotomy/laparoscopically

41. Enucleation
 Indications-
 benign
 Small, isolated tumors < 2 cm
 2-3mm away from mpd
 Located near surface of pancreatic parenchyma

42. PNETs- Body and Tail

44. PNETs – head

45. Median/central
Pancreatectomy

46. Management of metastatic
disease
 Lymph node mets are associated with increased recurrence.
 Recent studies suggest that a more aggressive approach may
benefit
 Hepatic metastasis- surgical debulking of hepatic disease is
prudent, in whom 80-90% reduction of metastatic disease is
made. Formal segmental resection is gold standard
 Other techniques – radiofrequency/microwave ablation, hepatic
artery embolization (<5cm)
 Liver transplant – 5 yr survival – 68%
 Predictor of poor outcome- location of primary in pancreas or
duodenum, need for upper abd exentration and hepatomegaly
Tsutsumi K, et al: Analysis of lymph node metastasis in pancreatic neuroendocrine tumors (PNETs) based on the tumor size and
hormonal production, J Gastroenterol 47:678–685, 2012.
Hashim YM, et al: Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors
(PNETs), Ann Surg 259:197–203, 2014.

47. Non surgical management
 Goal – improve quality of life, extend survival
 Insulinoma – diazoxide(200-600mg/day)
 ZES – PPI – titrated to effect
 Somatostatin based analogues – first line for nf met
 Octreotide
 Lanreotide
 Peptide receptor radionucleotide therapy- approved only in Europe
 Systemic chemotherapy –
 CAPTEM- Capecitabine temozolomide
 Grade 3 – cisplatin + etoposide
 Biologic therapies –mTOR inhibitors – EVEROLIMUS
RADIANT-3 trial – tumor shrinkage - 68%
 Sunitinib

48. Thank you