Zollinger Ellison Syndrome

DEFINITION
Gastrinoma --> PUD
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EPIDEMIOLOGY

Rare
Usually ~5th decade
- younger in MEN1 associated

Risk factors
1/3 of patients have MEN 1 (parathyroid, pituitary)

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AETIOLOGY

Secretion of gastrin by a neuroendocrine tumour

Gastrinoma
- in pancreas,
- or submucosally in the duodenum
- rarely at an ectopic site, e.g. antrum or ovary.

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BIOLOGICAL BEHAVIOUR

Pathophysiology

Gastrin leads to profound gastric acid hypersecretion
Causes PUD

Gastrin Physiology
Synthesized in G cells, endocrine cells primarily in gastric antrum.
Small numbers in duodenal mucosa.
Gastrin release is controlled by chemical, neural and mechanical stimuli
- stimulated by digestive proteins; phenylalanine and tryptophan
- by calcium and adrenaline
- by gastric distension
Inhibited by beta-blockade
Vagal parasympathetic control is both stimulatory and inhibitory.
- activation of vagal cholinergic reflexes by hypoglycaemia or sham feeding stimulates gastrin release
- atropine blocks release
- truncal vagotomy causes an increase in gastric secretion, incl food-stimulated; hypergastrinemia.
--> inhibits cholinergic inhibitory pathways
A variety of peptides also affect gastrin release
- bombesin (gastrin releasing peptide)
- inhibited by somatostatin, secretin, glucagon, gastric inhibitory peptide (GIP), vasoactive intestinal peptide (VIP)

Pathogenesis
May involve oncogenes, e.g. c-myc and Her-2/neu
And tumour suppressor genes, e.g. MEN-1 gene (most studied), DPC4/Smad, p16INK4a
Markers for aggressive behaviour include oncogenes, RET proto-oncogene, over-expression of EGF-R and IGFIr
- also chromosomal abnormalities

Men 1
This gene contains Menin, principally a nuclear protein that alters tumour growth factor beta signaling
Regulates nuclear factor transcription
And may function in DNA repair and synthesis.
Studied in familial and sporadic gastrinoma.
- MEN-1 associated endocrine tumours show loss of heterozygosity in 50% and 0-40% sporadic
Importance is due to hyperplasia-to-metaplasia transition.
Fundamental importance to familial and sporadic gastrinomas, but determinant of aggressive tumour growth or mets.

Natural History

All should be treated as potentially malignant.

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MANIFESTATIONS

1. Usually idiopathic PUD (75%)
- Haemorrhage, perforation and obstruction are common complications.

2. May get diarrhoea (25%)
- from the acid (destroys lipase and produces steatrrhoea).
- 5% = diarrhoea only

Often delayed diagnosis
- mean time of symptoms to diagnosis is 5 years.

Suspect if:
Diarrhoea, pain and weight loss.
Recurrent or refractory ulcers
Prominent rugal folds (trophic effect of gastrin)
GI symptoms in an MEN-1 patient
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INVESTIGATIONS

Biochem

Fasting Serum Gastrin
Avoid PPIs / H2 receptor blockers for 3d before measuring.
Insufficient alone to establish diagnosis
- i.e. sensitive but not specific
- achlorhydria can cause it (pernicious anaemia, atrophic gastritis, chronic pharmacologic suppression)
- so can H pylori, GOO with peptic ulcers, G-cell hyperplasia, short gut syndrome and renal failure (all associated with hypersecretion of acid)
Absolute level is not diagnostic
- 200 pg/mL = N
- only 30% of those afflicted have gastrin levels >1000 pg/mL
- 60% >500 pg/mL
--> ie these ranges not uncommon with other causes above.
Higher levels associated with degree of acid secretion, pancreatic primary, size of tumour, extent of disease
- but no influence on prognosis

Secretin provocation test
Stimulation of gastric in ZES, mediated through secretin receptors on gastrinoma cells.
No need to stop PPIs
Give a push (0.4mg/kg) by IV push, measure gastrin at 0. 2, 5, 10, 15, 30 min.
Increase of >120 pg/mL
- this is sensitive
Much better specificity (except that some achlorhydric pts also show increases.

Algorithm for Diagnosis

image

Imaging
CT or MR often shows the tumors.
Somatostatin-receptor scintigraphy is extremely sensitive for primary and metastatic sites
- but still unable to assess >1/3 of primaries
Difficult circumstances:
- use transhepatic portal vein sampling with secretin or calcium stimulation; invasive, measures gastrin gradients,
Overall success rate of pre-op localization is ~75%

Sensitivity of imaging

Test                Primary       Liver Metastases
US                      9                            46
CT                     31                           42
MRI                  30                            71
Angiography    28                            62
SS                     58                            92

EUS
High sensitivity for pancreatic leasions (?80%) but <50% for duodenal
Also allows cytologic dx

Recommendation
Order US, CT +/- MR,  EUS, SS +/- transhepatic vein sampling if still struggling.
No routine role for PET
- low sensitivity for localization.

Evaluation for MEN 1
25% of patients have MEN1
- many with no family hx
- ZES first manifestation in less than half.
--> many later go on to get hyperparathyroidism
So screen all patients with ZES for MEN-1
And measure:
- serum calcium
- parathyroid hormone
- prolactin

Histology
Histology patterns similar between benign and malignant, cancer dx made on metastatic invasion.

Staging
T1 <= 1cm
T2 1-2 cm
T3 2-3 cm
T4 >3cm

Stage
0 = T0N0M0
1 = T1 anyN M0
2 = T2-3 anyN M0
3 = T4 anyN M1


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MANAGEMENT


Principles
PPI for acid secretion
Surgery for cancer control


Medical
High dose omeprazole
- titrated to symptoms and ulcer healing.
With long periods of therapy, may need to check B12

Surgical

Gastrinoma triangle
image
Most are here.
Duodenum, pancreas (head & uncinate process) up to porta.

1. Work-Up and Warn
Work up with CT or MR of pancreas and somatostatin-receptor scintigraphy.
--> Imaging of primary possible in ~3/4
Offer surgical exploration to these patients

2. Also advise surgery when cannot find a primary
- but warn that may not locate it (15% no find rate in -ve imaging patients)
- Tumours may be as small as 2-3 mm and hard to find
Principles of exploration
- Kocher to examine head of pancreas and uncinate process
- mobilise body and tail of pancreas to allow bimanual palpation.
- intra-operative USS
- longitudinal duodenotomy and palpation of mucosa (often
- sampling of nodes from gastrinoma triangle

3. If Duodenal Gastrinoma
Most common location
Hence evaluation in occult disease mandatory
Us. in 1st - 2nd part; but can be 3rd-4th
Lateral duodenotomy; longitudinally 3-4cm
- extend proximally or distally to allow better exposure for removal.
Mucosa inspected visually, often small lesion <2mm, usually <1cm.
- Brunner gland hyperplasia may look like a lesion but isn't.
Excise, and send for frozen section, continue inspecting as there may be a field change.
Explore porta within triangle and excise nodes
Assess pancreas by palpation and ultrasound.

4. Lymph Node Primaries
Primary nodes in ~10%.
Not in MEN
Tentative diagnosis... may simply be nodal disease from occult primary; will show within 10y follow up.
Yearly assessment with fasting and secretin-stimulated serum gastrin.
Long term disease-specific survival possible.

5. Pancreas Primary
50% in pancreas
Expose pancreas, IOUS.
Still need to do a duodenotomy to look for another primary...
Enucleate anything <2cm in uncinate process or head, unless involving the duct.
Lesions in body and tail are usually near pancreatic duct and require pancreatectomy and splenectomy.
Role of Whipple's is controversial
- most centers do not recommend it.
- Based on patient and disease factors.
--> probably best to avoid radical surgery given its indolent course.

Results of Surgery
Definition of biochemical cure is normal fasting and secretin-stimulated gastrin.
Only ~50%
Recurrence in 40%
Surgical resection increases disease-specific survival;
- 98% for operated; 74% non-operated at 15y and 60% vs 20% at 20y.

MEN-1
Hyperparathyroidism requires surgery
- manage this initially and gastrinoma will already improve.
- subtotal or total and auto-transplantation.
Controversy regarding role of gastrinoma surgery in MEN-1
- cure rates much lower; ~10%
Role of surgery is define by imaging
- image-negative pts should be observed and not undergo exploration; low cure rates.
- image-positive pts with no mets to liver or bone should undergo surgery; improves survival
Low cure but prolonged survival.

Treatment of Hepatic Mets
Options are resection, radiofrequency ablation, hepatic artery embolization, chemoembolization, liver transplant, chemo, radiolabelled somatostatin.
Most studies include other neuroendocrine tumours and carcinoids.
Consensus is that surgical resection improves survival
- 5y survival ranges from 70-100%
- poor prognostic factors are age>50, bilobar disease, extensive disease burden
Low level evidence supporting transplantation.
- selective patients who don't respond.

Debulking in Extensive Metastatic Disease?
no role.

Prognosis
70% have immediate biochemical cure, 30% disease free at 5 yrs.
Rest depends on cancer status
- many live a long time due to relatively indolent course.
Stage 1 10y survival 80%
Stage 2 70%
Stage 3 30%
May be curable when mets in peripancreatic nodes or liver.
Rarely curable in MEN 1.
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REFERENCES
Doherty.