A presentation for Post Graduate General Surgery Residents about the Pancreatic Neuroendocrine Tumors.

1. Pancreatic Neuroendocrine
Tumors
Nabin Paudyal

3. Introduction
• < 3% of total pancreatic neoplasms
• Incidence increased more than 7 folds in last 2 decade because of
• Increased awareness among physicians
• More frequent CT/ MRI use
• Improved sensitivity of Immune Histochemistry and Radiological diagnostic
testing
• Broadly classified as
• Functional
• Non-functional tumors

4. Histopathology and staging
• Malignancy in PNETs can only be determined by the PRESENCE OF
METASTASIS
• 2010 WHO staging system is most widely used staging system for
NETs

5. Advantages of WHO grading
• All NETs irrespective of tissue of origin or functional hormone
secretion are included
• Classification is based on differentiation and grade
• Appearance
• Mitotic rates
• Invasion to other organs
• Angioinvasion [to celiac/ SMA]
• Ki-67 proliferation index [@ AMIKA]
• Poorly differentiated tumors are referred to as ”Neuroendocrine
carcinoma”

6. Molecular genetics of PNET
• Mostly sporadic
• If a/w genetic symptoms
• MEN 1
• PNET, pituitary adenomas, parathyroid adenoma (and hyperplasia)
• MENIN gene (Chr 11)
• Autosomal dominant
• G1 S phase cell cycle control is disrupted
• VHL
• RCC, pheochromocytoma, CNS adenomas, Pancreatic lesions
• Specific germline mutation in exon 3 of VHL gene may be associated with more aggressive
phenotype and warrant earlier treatment and close surveillance
• PNET associated with VHL gene can be observed until tumor is 2-3 cm in size

7. • Tumorigenesis
• involves accumulation of several genetic events Inactivating mutations (mTOR, DAXX,
ATRX, FAK/Src) and impacted signal transduction pathways malignant transformation

8. General principles of diagnosis and treatment
of PNET
• Diagnosis and evaluation
@ H-C-M-F

9. A
P
P
R
O
A
C
H
T
O
P
N
E
T

10. Screening for functional tumors
• In patients with HYPERENHANCING PANCREATIC mass on cross
section, H/O neuroglycopenic symptoms, diarrhoea, ulcer diathesis,
rash (@ RUN-D) and other symptoms suggestive of classic hormonal
syndrome MUST BE taken
• Family H/O
• Laboratory investigations for  Chromogranin A, Neurotensin, PP

11. Localization of tumor
• Vast majority will be identified on cross-sectional imaging
• Imaging with CT or MRI is first step in localization
• CT hyperattenuating, vascular blush capture in arterial phase
• MRI Low signal intensity on T1-weighted image and high signal intensity on T2-weighted
image
• EUS Better sensitivity for tumors < 3cm, especially insulinomas and allows fine-needle
aspiration of tumors
• Other imaging adjuncts
• Somatostatin receptor scintigraphy (SRS) useful for most PNET excepting insulinoma (as
insulinoma doesn’t have somatostatin receptor)
• SRS is limited by physiologic sites, lacks anatomic precision in localization
• SPECT Single photon emission CT can be used to delineate anatomic precision
• Angiography Can be useful in detecting insulinomas larger than 5mm.

14. Some other special localization techniques
• Portal venous sampling
• Assess for insulin and gastrin levels
• Aids in operative planning
• Arterial stimulation by calcium OR secretin injection into celiac OR
SMA.
• Helps localize tumors
• Principal: Calcium stimulates insulin secretion

15. Management of PNET

16. a. Non-metastatic, symptomatic localized
PNET
• Surgical resection
• Approach and extent of resection is directed by the functional status
of the tumor, type, location, stage, grade and patient factors
• Principle of surgery
• Partial pancreatic resection (head or distal pancreas OR enucleation)
• Open or minimal invasive
• Remove primary tumor with regional lymph nodes

17. b. Incidentally found and localized, small, Nonfunctional
PNET
Ki-67 is < 10%
Observation criteria
a. < 2cm
b. G1 or Low G2
c. Asymptomatic
d. No imaging finding
suggestive of
malignancy

18. c. Non metastatic PNET-unlocalized Pre-
operatively
• Intra operative USG
• Detected as sonolucent mass, generally uniform in consistency
• Initially Pancreas mobilization is done
• Surgical removal of tumor

19. Metastatic disease
• 40-80% are detected at the time of diagnosis
• Liver MC site for metastasis
• Long term outcomes for NET liver metastasis is more favorable than liver
metastasis for adenocarcinoma
• Aggressive therapy warranted
• Multidisciplinary care
• Combined approach involves aggressive surgical resection, ablative-liver
directed therapy, cytotoxic OR targeted chemotherapy

20. Liver surgery for metastatic disease
• Surgery Either palliative OR curative
• Curative surgery is possible in 10-25% of patients with liver metastasis
• Criteria
• G1/G2 tumors
• Absence of distant LN metastasis
• Absence of extrahepatic or peritoneal metastasis
• Resection is recommended if >90% can be removed
• Resection can be
• Bulk removal of tumor
• Staged removal
• Bilobed metastasis are usually resected using staged removal Portal vein embolization f/b
staged resection on each side

21. Ablative-Liver directed therapy for metastatic
disease
• Alternative to liver resection includes other liver-directed therapies
such as RFA, cryoablation, TAE, TACE (chemoembolization) and
Radioembolization
Radiofrequency ablation

22. • Reserved for patients with symptomatic disease that is not amenable to
surgical resection
• RFA can treat unresectable mass < 5cm and is effective in controlling
symptoms related to hormone secretion
• Transcatheter transarterial therapies are well suited to metastatic liver
diseases.
• Embolization uses Lipoidol, gel foam particles, polyvinyl alcohol foam or bland
microspheres
• Chemoembolization uses doxorubicin, melphalan, streptozocin
• Selective intra-arterial radiotherapy Embolization with Y90 microspheres.

23. Cytotoxic and targeted systemic therapy
• 5 types octreotide receptors have been identified
• SSTR 1-5 receptors
• Octreotide and Lanreotide SSTR 2 and SSTR 5
• Pasireotide SSTR 1, SSTR 2, SSTR 3 and SSTR 5
• PROMID study Long acting somatostatin analog was found to
increase time to progression in pts with metastatic well-
differentiated PNETS.

24. • Tumor are Grade1 or 2.
• Regardless of HEPATIC TUMOR VOLUME

25. For poorly differentiated NET
• Respond better to cytotoxic chemotherapy than well-differentiated PNET
• Various cytotoxic agents are used in treating unresectable PNETS
• Streptozocin, Cisplatin, Dacarbazide, Doxorubicin and 5-FU [@F-DCDS]
• Temozolomide alone OR combination with Capecitabine  70% response rate
• For high grade tumors Platinum-based regimens (e.g. Cisplatin with Etoposide)
• Targeted therapies Everolimus (mTOR inhibitor), Sunitinib (Anti-
VEGFR, anti-PDGFR, CD-117 and CD-135)
• Radiolabeled somatostatin analogs in patients with strong radiotracer
uptake in somatostatin receptors Y90 and Lutetium

26. Liver Transplantation for metastatic PNETs
• Even after treatment of liver metastasis recurrence in remnant liver is
common within 2 years
• Hepatectomy with liver transplantation has been proposed as a potentially
curative treatment option for unresectable PNET
• UNRESECTABLE NEUROENDOCRINE METASTASIS IS THE ONLY METASTATIC
INDICATION FOR LIVER TRANSPLANTATION
• Milan Criteria for liver transplantation
• Age < 55 years
• Well differentiated tumors
• Ki-67 proliferation index < 5%
• Completely resected primary tumor with portal drainage
• Less than 50% liver involvement
• Absence of extrahepatic disease

28. MEN 1 associated with PNET
• 30-80% are a/w MEN1 and are most common cause of tumor-related death.
• Usually PNET a/w MEN-1 have
• Younger aged patients
• Multicentric, multiple
• Malignant potential
• Metastatic
• Most common PNET seen with MEN-1
• Non-functional PPoma
• Functional Gastrinoma, Insulinoma, Glucagonoma, VIPoma

29. Management
• Laboratory investigations
• Biochemical screening for gastrin, insulin, PP, glucagon, chromogranin A
• Screening Calcium level, Parathyroid hormone level
• Radiological
• Sestamibi parathyroid scintigraphy
• Treat hyperparathyroidism first
• Surveillance
• Annual EGD and remove large lesions
• If malignant appearing Surgery