Pancreatic neuroendocrine

tumors
 Pancreatic neuroendocrine PNETS- <3% OF pancreatic neoplasms.

PNETs- 7% of all gastroenteropancreatic tumors.

PNETs- broadly classified into functional and non functional.

Introductio
n:
F-PNETs- secretion of hormones by functional tumors leads to the characteristic syndromes and
physiological derangements.

Immunostaining often identifies multiple hormone products, even in the absence of a clinically
relevant hormone secretion.

Non functional tumors- asymptomatic at diagnosis, incidential finding or local symptoms due to pain,
mass effect, biliary obstruction.
Syndromic associations are commonly seen with MEN1, VHL syndrome, tuberous sclerosis,
Neurofibromatosis1.
Histopathology:
• Incidence of malignancy in insulinoma is 10%, meanwhile its 100% in
glucagon or somatostatin secreting tumors.
• 2010, WHO staging system- includes all site of origin, functional hormone
secretion, classification based on differentiation and grade.
- High grade/ poorly differentiated PNETs are sometimes referred to as
neuroendocrine carcinomas ( <3% of PNETs).
- Well deferentiated tumors do still have malignant potential but that the
differences in behaviour persists, even for patients with metastatic disease.
• AJCC and ENETS staging- do not include tumor grade, both apply staging
similar to exocrine pancreatic cancers.
• 8th edition AJCC staging sytems exhibited good prognostic discrimination
across stages in both resected and unresected patients.
 CELL TYPES SECRETION TUMOR- PNET CLINICAL SYNDROME
A- Alpha cells 25% Glucagon Glucagonoma - Peptic ulcer, diabetes, necrolytic migratory
erythema (low aminoacids levels)
- > 500pg/mL.
- Octreotide for palliative care.

B- Beta cells. 50% Insulin Insulinoma Whipple triad- symptomatic hypoglycemia, BGL
<50mg/dL, Symptomatic relief.
Increased Insulin + C- peptides.

D- Delta cells. 10% Somatostatin Somatastatinoma Cholelithiasis, steatorrhea, DM.

S. Somatostatin > 10ng/mL
F- cells Pancreatic polypetide PPoma
D1 cells VIP- vasoactive intestinal VIPomas WDHA – Werner Morrison syndrome
peptides Watery diarrher, hypokalemia, achlorhydria.
G cells Gastrin Gastrinoma Zollinger Ellison syndrome – fulminant PUD,
acid hypersecretion, non beta islet cell tumors
Passaro triangle.
 PNETS- have varied presentations; Symptomatic, functional, mass effects,
metastatic disease.

DIAGNOSI
S AND History- gives neuroglycopenic symptoms suggestive of functional tumors
as such diarrhea, ulcer diathesis, rash, flushing, classical hormonal

TREATMEN syndrome.

T: Screening for gasto intestinal peptides: Chromogranin A, pancreatic

plypeptides etc.
- Chromogranin A: found both in functional and non functional PNETS,
confirmation of diagnosis, prognostic value in recurrances, also elevated in
proton pump inhibitors, atrophic gastritis, heart or renal failure.
• Locatization:
1. MDCT: 73- 96% sensitivity. PNET have rich vascular supply- presents as hyperattenuating
lesions.
In case of small lesions (Insulinomas/ Gastrinomas) 1.25mm collimation cuts, multiple
phases imaging.
Insulinomas- have pronounced arterial blush, and reduced venous attenuation.
Water instead of oral contrast helps in identification of small duodenal gastrinomas.

2. MRI: sensitivity of 80-90%.

T1- low intensity and T2 high intensity.
CT and MRI – size is directly related to sensitivity in identifying small sized lesions.
• 100% sensitivity in 3 cm lesions, 50% in 1-2 cm lesions, nil in < 1 cm lesions.

3. EUS: sensitivity- 90% in all sizes. With FNAC feasibility.

best diagnostic performance in localization of EUS.
least diagnostic sensitivity- 50% in small duodenal tumors.

4. Somatostatin receptor scintigraphy: 80% sensitivity in all tumors, >90% specificity in

gastrinomas, glucagonoma, non functional tumors, differentiation of hepatic metastasis
from non insulinoma PNETS.
Presence of somataostatin receptors are absent in Insulinomas, pancreatic
adenocarcinomas.
 5. SPECT (hybrid single proton CT) – in G1 /G2 tumors, SPECT shows 96% sensitivity and 97%
specificity.
SPECT shows high anatomical locations and tumour lesions and physiological uptake.

6. Angiography -70% sensitivity in > 5mm in insulinomas.

7. portal vein sampling: 88-90% sensitivity

For assessing insulin or gastrin levels. Arterial stimulation with iv gastrin or secretin via Celiac or
superior mesenteric artery followed by portal vein sampling. Helps us in localizing the tumor as well.

8. Nuclear medicines: Octreotide scan, FDG PET scan, 18F DOPA, 68G- Octreotide (NETSPOT),
NETTER Trail 1 peptide receptor radiotherapy.
 Serum biomarkers:
General biomarkers Specific biomarkers

Chromogranin A: ENETS- diagnosis and follow of NF- NETS. INSULIN- HYPOGLYCEMIA (72 hr fasting test- gold standard)- 12 hrs
Independent prognostic factor of PFS and OS. >15ng/mL from fasting Whipple triad (48hrs): S/S of hypoglycemia, low plasma
baseline as significant predictor of OS. glucose, resolution of symptoms after corrections.
Preop CgA in post op recurrence was higher. Glucagon: >500 pg/mL , high malignant potential. A/s MEN1.
Glucagonoma syndrome.

Neuron specific enolase: low diagnostic sensitivity of 33%. A/s with VIP: Verner Morrison syndrome/ pancreatic cholera syndrome. 50-
poor differentiation and shorter PFS. 89% has liver and lymph node metastasis.

Progastrin releasing peptide: precursor of GRP- Small cell carcinoma Gastrin: duodenum> pancreas. Zollinger Ellison syndrome, 1000 x
lung. A/s with tumor grade in NENs. increase in s. gastrin is diagnostic.
Secretin test: > 120pg/mL from baseline is diagnostic.

Pancreatic polypeptide: @ head and uncinate. PP+ CgA- Increases Somatostatin: Hyperglycemia, Cholelithiasis, maldigestion of foods.
sensitivity by 25% in NF NETs. 84% specificity for DCR. Ectopics: ACTH (Cushings), GRH (Acromegaly), Carcinoid and Phrp.
• Novel biomarkers- Circulating tumor cells, NETests, microRNA, cytokines.

• Incidential findings small non functional PNETS: surgical resection is mandatory as they
all have malignant potential. Increased identification of incidential and asymptomatic
tumors provides potential overdiagnosis and overtreatment.
Role of observation in small in non functional tumors have been well noted.

• 2016 ENEIS: in G1/ G2 with low ki67<10% observations with serial 3-6 monthly EUS+ MRI
,followed by every 12months if constant.
> 0.5 cm requires reevaluation for resective surgery.
• NCCN guidelines suggests in routine checkups every 6-12 months, adequate history
taking, CT/MRI and CT chest if indicated.
• 5 year progressive free survival: incidential tumors had a 86% PFS, while 59% in
symptomatic tumors.
• Most common operative complication was pancreatic leaks
• Zhang and collegues, mentioned the value of resection of PNETS >1.5 cm improved
survival but not so for > 1.5cm tumors.
Non metastatic symptomatic –
localized preop
• Includes tumors which are symptomatic and functional.
• Rx:
- surgical resection.
- partial pancreatic resection: Head, distal pancreatectomy, enucleation.
( Enucleation prevents the removal of regional lymph nodes and helps in preserving
pancreatic parenchyma)
- splenectomy with distal pancreatectomy if nodal clearance is difficulty.
Non metastatic unlocalized preop.
• Use of intra op USG, using 7.5-10 MHz for pancreas after complete mobilization, 5MHz
liver.
Ductal system will be seen as a lucent tube without flow in a doppler.

• LIVER METS:
- Most common, 60-80% at diagnosis. Has both a palliative and curative roles (10-25%)
- Resection of lesions is recommended if >70% is resectable.
- Bilobular mets require staged resection, primary resection of the tumor with portal vein
embolization followed by staged resection.
RADIOFREQUENCY ABLATION-
unresectable < 5cm, symptomatic
control.

TRANSARTERIAL EMBOLIZATION High vascularity and multifocal lesions, best approach.

Lipiodol, Gel foams, Bland microspheres (Drug/ Yttrium 90)
- Intramural concentrations reach 20x higher.
- High partial pressure rates
- Improvements in symptomatic relief.

TRANSARTERIAL CHEMOEMBOLIZATION Doxorubicin, melphan, streptozocin

RADIOEMBOLIZATION/ Y90 microspheres shows 55% response, with overall control

SELECTIVE INTRA ARTERIAL RADIO EMBOLIZATION: seen in 88-90% at months.
 Cytotoxic drugs
SOMATOSTATIN ANALOGUES: controls hormonal secretion and stabilizes - Octreotide, Lanreotide, Pasireotide.
tumor growth. - PROMID: LA SSA demonstrated increases time to progression in
SSTR ( 1 2 3 4 5 ) patients with WD metastatic PNETS.
- CLARINET: Lanreotide prolonged PFS, regardless of hepatic margins in
* Oct/ Lanreotide has affinity for SSTR 2, binds with SSTR 5 Metastatic G1 / Low G2 lesions.
- LA SSA: Prophylactic cholecystectomy.

- STREPTOZOCIN + 5 FLUROURACIL + EPIRUBICIN -> 20-50% in G1/ G2

- TEMOZOLOMIDE + CAPECITABINE -> 70% in G1/G2 with PFS 18 months, 2 years OS at 94%
-> For high grade tumors, 42- 67%
- PLATIN based regimen: CISPLATIN + EPOSOMIDE

mTOR Inhibitors EVEROLIMUS

Longer PFS >11 months
Given with somatostatin analogues.

Tyrosine kinase Inhibitors SUNITINIB

(PDGF, VEGFR, protooncogene- CD117, CD135) Larger PFS > 11 months
PRRT
Immunotherapy- SURUFATINIB, CABOZANTINIB
• Liver transplantation: in unresectable NETs, only metastatic indication for liver
transplantation.

- MILAN criteria: 5 year survival is 90%.

1. < 55 years
2. well differentiated/ Ki 67 < 50%.
3. completely resected primary tumor with portal drainage.
4. <50% liver metastasis
5. no extrahepatic diseases.
Non insulinoma pancreatogenous
hypoglycemia syndrome
• Insunlinoma is the mc. of hyperinsulinemia hypoglycemia.
• Nesidioblastomsis- excessive pancreatic B cells symptoms.
• Primarily in infancy, but seen in cases of bariatic surgery.
• Have a positive 72 hour fast with episodes of hypoglycemia, with
inappropriate elevation of insulin, C – peptide, proinsulin levels.
• 95% distal pancreatectomy, dietary control, diazoxide and
somatostatin analogues.