PNETs

DEFINITION

PNETs except gastrinoma discussed here.
Used to be called pancreatic islet cell tumours.
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EPIDEMIOLOGY

Rare, except in MEN families
5-25% associated with genetic syndromes.
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AETIOLOGY

Neuroendocrine tumours.
See here for gastrinoma
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BIOLOGICAL BEHAVIOUR

Functional Types

1. Insulinoma
Most common functional neuroendocrine tumours.
Almost always in pancreas (99%)
Whipple's triad = hypoglycaemia, neuroglycopenic syndrome, relief of symptoms with glucose.
- neuroglycopaenic syndrome = fancy word for neurological problems due to hypo's, e.g. fatigue, confusion, blurry vision, weakness, seizures.
Diagnosed by low BPs in face of inappropriately elevated insulin (>5mU/mL)
- ideally need a 72h fast, in hospital, and bloods drawn every 6h for glucose and insulin monitoring.
--> once they get neuroglycopaenic symptoms, measure these again and then give IV glucose and terminate fasting.
--> IV glucose should treat symptoms.
Typically <2cm at diagnosis and often multiple in MEN
90% are benign.

2. Glucagonoma
Almost always in pancreas
Usually malignant (>70%)
Cause a characteristic rash called necrolytic migraotry erythema.
- erythematous rash affecting perioral, pretibial and intertriginous areas.
- often precedes other features by years.
Causes severe hypoaminoacidaemia, with weight loss, type II DM, and cachexia.
High risk of DVT/PE
Diagnosed with high serum glucagon and low levels of amino acids.
Most have large 5-10cm tumours at diagnosis that may not be amenable to surgery.

3. Pancreatic polypeptide secretin tumor
Rare
Pancreatic polypeptide secretion causes no symptoms and goes unnoticed.
Essentially considered nonfunctional.
May present later with a pancreatic mass, weight loss, bleeding obstruction or pain.
Tumours usually diagnosed incidentally.
>50% malignant.
Diagnosed by fasting pancreatic polypeptide levels, definitive diagnosis is immunohistochemical.

4. VIPoma
Overproduction of VIP produces massive secretory diarrhoea.
Known as WDHA syndrome
- Watery Diarrhoea, Hypokalemia, Achlorhydria
Diarrhoea volume is intense; 5-10L per day, associated with electrolyte abnormalities.
Very rare, and may occur in pancreas (mainly) or duodenum.
Diagnosed by fasting plasma VIP levels with symptoms.
Commonly malignant (50%)

5. Somatostatinoma
Very rare.
Cause steatorrhoea, cholelithiasis, DM II and hypochlorhydria.
Typically malignant tumours (>90%) that present with stage IV disease.
In duodenum, associated with Von Recklinghausen disease (Neurofibromatosis).

6. Extremely rare PNETs
Eg ACTHoma, PTH-oma, serotonin, GHRH.
- can present with Cushing's, hypercalcaemia, flushing, and acromegaly respectively.

7. Non-functioning PNETs
Relatively common PNET.
Don't present until there is a mass; usually large and malignant
- e.g. bleeding, obstruction of bile duct or duodenum
Distant mets often present; liver.

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MANIFESTATIONS

As above
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INVESTIGATIONS

Imaging

Insulinoma
Very small localization problematic.
Pancreatic protocol Ct.
PNETs are hypervascular, so blush on arterial phase, ie a very bright round spot in the pancreas
- so contrast scan can have high sensitivity of >80%
Somatostatin receptor scintigraphy has high sensitivity for PNETs = poor method for imaging insulinomas.
EUS = useful in right hands; less sensitive for tail lesions
- sensitivity 80-90%
Biopsy, if achieved, makes diagnosis unequivocal.
Intra-operative USS is most sensitive detection method; shows relationship of tumour to main structures and can delineate safe routes for enucleation.
- indicated even if preop localization studies uninformative.

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MANAGEMENT

1. Pre-op Prep

Insulinoma
Control hypoglycaemia, frequent small meals, including awakening at night to eat catbs.
60% respond to octreotide
VIPoma
Fluid and electrolyte resuscitation.
Dehydration may be so severe that cannot be managed with IV fluids alone.
Need ocreotide.
Glucagonoma
Often present with severe malnutrition, must have TPN and insulin prior to surgery.
This will fix the rash.

2. Principles
More advanced burden = more major resection.
Concomitant liver resection may be needed.
Surgery is only potentially curative option
- consider surgery in all patients.
Even pts with mets may benefit from surgery; less likely if distant, but debulking is palliative and may prolong survival.

3. Operative Approach
Localize.
Enucleate benign tumours (e.g. insulinomas), preserving pancreas and spleen
- intraop USS should facilitate rsection.
If metastatic to liver, mets may be resected.
- treat with wedge resection, lobectomy, or if unable, then RFA, chemoembolization.
--> survival will be 60-70% at 5 years, so relatively good.
>90% of pts can have relatively good surgical outcomes with correction of symptoms even if unable to remove all gross disease.

4. Adjunctive Rx
Standard chemo used tith modest effect.
E.g. 5FU, doxorubicin.
- encouraging result from xeloda, oxaliplatin, avastin.
Somatostatin analogues may stabilize disease without inducing regression.

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REFERENCES