Zollinger – Ellison Syndrome

Eduardo A. Guzman MD

Robert Milton Zollinger1903 - 1992

• Giant of american surgery

• “He was respected by his

peers, feared by his

students and loved by his

patients”

Robert Milton Zollinger

• Born on September 4, 1903

in Millersport, Ohio

• He attended grade school in

a one room schoolhouse

• Graduated in medicine from

the Ohio State University

Robert Milton Zollinger

• Internship at Peter Bent Brigham Hospital

• Interns were not allowed to get married

• In 1929 he married Louise Kiewet at the conclusion of his internship

Robert Milton Zollinger

• Residency at Western

Reserve University

• Chief resident at Harvard

with Dr Elliot Cutler

• Cutler and Zollinger

published the first edition

of the ¨Atlas of Surgical

Operations¨

Robert Milton ZollingerMilitary

• Joined the army in 1941

• Commanded the 5th general

hospital

• Legion of Merit Award– Mobile surgical teams

• Battle Stars – Normandy

– Northern France

– Rhineland

Robert Milton Zollinger

• Ohio State

• Chief of Surgery

Robert Milton Zollinger

• President

– American Board of Surgery

– American Surgical Association

– American College of Surgeons

• Sheen Award – Highest honor of the AMA

• Offered the presidency of the Ohio State University which he

turned down

• Training Dr Sirinek

Robert Milton Zollinger

• Perfectionist

• Competitive

• Humane

• Died in 1992 of pancreatic

cancer

GASTRINOMA

Recent advances and ongoing controversies

• 1954

• Ohio State University

• Dr Robert Zollinger

• Dr Edwin Ellison

Discovery

Southern Surgical Association

• 1955

• 2 patients with a clinical triad of

– Benign jejunal ulcers

– Extreme acid hyper secretion

– Non β Islet cell pancreatic tumors

Gastrin

• Gregory 1960

• G cells

• Gastric antrum

• Acid release

• 1976 Gastrin Radioimmunoassay

• Tumor

– ¾ malignant

• Incidence

– 2 per million population

– 0.1 % of patients with duodenal ulcers

– 2 % of patients with recurrent ulcers

• 80 % sporadic

• 20 % as part of the MEN 1 syndrome

Gastrinoma

Identification

Treat

Localize

Diagnose

Identify

↑ Gastrin

↑ Gastric acid

Duodenal ulcer Bowel mucosal injury

Bleeding Diarrhea

Pain Malabsorption

Complications

Pathophysiology

Clinical syndrome

• Manifestations of peptic ulcer disease

– Pain

– Bleeding

– Obstruction

– Perforation

• Diarrhea

• Malabsorption

Diarrhea

• Not typical for ulcer disease

• A prominent feature of Zollinger

Ellison syndrome

Clinical syndrome

• Patients are often times misdiagnosed – Crohn’s– Irritable bowel syndrome– Celiac sprue– Lactose intolerance

• A high index of suspicion is required to make the diagnosis

Clues

• Diarrhea

• Ulcers in atypical locations

– Distal duodenum

– Jejunum

• H Pylori negative

• Failure of medical management

• Recurrent ulcers

• Hyperparathyroidism

Impact of antacid therapy on the presentation of gastrinomas

• Less dramatic presentation

• Complicating the diagnosis of

gastrinoma

• More patients with advanced

disease

• Lower survival

C. Ellison. The American Journal of Surgery 2003

Study Period

1955–65

Discovery

1966–75

Recognition

1976–85

Gastrin RIA

1986–98

Medical tx p value

Patients (n) 11 27 21 49

Metastasis 45% 56% 19% 55% 0.030

5-year survival 45% 74% 90% 69% 0.052

5-year disease

free survival

0% 4% 29% 2% 0.003

The American Journal of Surgery. 2003

Diagnosis

• ↑ Gastric acid

• ↑ Gastrin

Treat

Localize

Diagnose

Identify

Diferential diagnosis for hypergastrinemia

• Gastrinoma

• Pernicious anemia

• Renal failure

• G cell hyperplasia

• Atrophic gastritis

• Retained gastric antrum

• Gastric outlet obstruction

• Use of acid suppression medications

Gastrin Radioimmunoassay

• Off acid suppressing medicines for 48 hours

JE McGuigan. New England Journal of Medicine 1968

< 200 pg/ml Normal

200 – 1000 pg/ml Confirmatory test (70%)

>1000 pg/ml Gastrinoma (30%)

Secretin stimulation test(Confirmatory test)

• Normally, secretin ↓ gastrin

• In gastrinoma, secretin ↑ gastrin

• Intravenous secretin

• Measure serum gastrin at regular

intervals

• A rise of 200 pg / ml confirms the

diagnosisCW Deveney. Annals of Internal Medicine 1977H Frucht. Annals of Internal Medicine 1989

Tests for gastric hypersecretion

• Basal gastric output

– >15 mEq/h if no previous

surgery

• Maximal gastric outupt

• BAO/ MAO ratio

– > 0.6 = ZES

Localization

Treat

Localize

Diagnose

Identify

Gastrinoma triangle

• A – Junction of cystic duct

and CBD

• B – Junction of second

and third portion of

duodenum

• C – Junction of body and

neck of pancreas

Location, location, location

JA Norton. The New England Journal of Medicine 1999

• National Institutes of

health

• 123 patients

• Duodenum 47 %

• Pancreas 14%

• Lymph node 13%

• Other locations 9 %

• Unknown 16%

Localization

Can be found anywhere in

the body

• CT

• MRI

• US

• Angiography

• Somatostation Receptor

Scintigraphy

Somatostatin Receptor Scintigraphy“Ocreotide scan”

• Gastrinomas have

somatostatin receptors

• Radioactively labeled

ocreotide

• Single most sensitive study

• Misses small duodenal

gastrinomas

B Termanini. Gastroenterology 1997

Somatostatin Receptor Scintigraphy

Sensitivity

SRS

CT MRI Angio

US

SRS + CT

0%

20%

40%

60%

80%

100%

Primary tumor

JA Norton. The New England Journal of Medicine 1999

Somatostatin Receptor Scintigraphy: Its Sensitivity Compared with That of

Other Imaging Methods in Detecting Primary and Metastatic

Gastrinomas: A Prospective Study

F Gibril. Annals of internal medicine 1996

Operative exploration

• 70 % preoperative localization

• 20 % Intraoperative localization

• 90 % succesful localization

Conduct of the operation

• Thorough abdominal exploration

• Liver ultrasound

• Bimanual palpation of pancreatic head and uncinate

• Pancreas ultrasound

• Anterolateral duodenotomy with mucosal palpation

• Removal of peripancreatic and periduodenal lymph nodes

• Frozen section analysis

Treatment

Treat

Localize

Diagnose

Identify

Tumor resection

• Pancreas head

– Enucleation

• Pancreas Body or tail

– Distal pancreatectomy

• Duodenum

– Full thickness excision

• Gastrectomy not required

Annals of Surgery 2006

Duodenotomy

• Dr Norman Thompson

• University of Michigan

• The primary location for

gastrinomas is in the duodenum

• Imaging studies miss small

duodenal gastrinomas

Annals of Surgery 2004

Postoperative management

• Standard postoperative care

• At least 2 serum gastrin levels

• Secretin stimulation test

• Fasting serum gastrin and secretin stimulation test in 6

months

Metastases

• 60 – 85 % of gastrinomas are

malignant

• Hepatic metastases predicts

survival

• Localized liver metastasis should

be considered for surgery

Effect of liver metastases on survival

• Liver metastases are the

#1 predictor of overall

survival

• Patients with diffuse liver

involvement do worse

F Yu. Journal of Clinical Oncology 1999

S Musunuru. Archives of Surgery 2006

Prognosis

• Extent of disease

– Large tumors

– Metastases

• Biologic characteristics

– Benign / malignant

– Aggressive / Non aggressive

– MEN 1 syndrome

• Surgical therapy

– Complete / Incomplete resection

Journal of the American college of surgeons 2005

Summary

• Monterrey is a nice place to live

• Dr Zollinger was a good man

• Gastrinoma is a malignancy

• A high index of suspicion is required for diagnosis

• More common in the duodenum

• A duodenotomy should be routinely performed

• Tumor resection improves survival

• Liver metastatectomy should be considered

• Prognosis is good if completely resected

Controversy 1What is the role of Endoscopic Ultrasound as preoperative

localization method?

FOR• It can identify depth of invasion

and obtain tissue diagnosis

AGAINST• Sensitivity

– Pancreas 75%– Dudenum 46 %

• Misses small duodenal gastrinomas (same as SRS)

• Pancreatic gastrinomas would have been detected by conventional imaging

MY ANSWER•Only in MEN 1 patients (multiple tumors)

Controversy 2Should patients with gastrinoma and MEN1 syndrome

undergo routine surgical resection?

FOR• Metastatic neuroendocrine

tumors are the predominant cause of death in patients with MEN1

AGAINST• Cure is rare in patients with

MEN1 – Multiple tumors

• Less aggressive nature of tumors• 100 % 15 year survival if tumor <

2.5 cm and no surgical exploration

MY ANSWER•No •Surgery if greater than 2.5 cm only

Controversy 3 What is the role of endoscopic resection of small duodenal

gastrinomas?

FOR• Biochemical cure can occur

AGAINST• Misses lymph nodes• Risk of duodenal perforation

MY ANSWER •Do not try it

Controversy 4Should a Whipple procedure be performed for the Zollinger

Ellison syndrome?

FOR• Whipple may provide a better

chance of cure and increased survival since it removes all the nodes.

• For MEN 1

AGAINST• Survival already good after

current surgery– Sporadic 10 yr 95%– MEN 10 yr 86%

• Makes reoperations more difficult

• Negates hepatic chemoembolization if liver mets develop

MY ANSWER•No•Only for patients that cannot be treated by simple enucleation

Controversy 5What is the role of surgery for advanced disease?

FOR• Liver metastasis is the most

important predictor of survival• Patients with diffuse liver

metastasis have significantly worse prognosis

• Slow tumor growth• May improve symptoms• May increase survival

AGAINST• Does not provide cure• Surgical morbidity

MY ANSWER•Yes•In selected patients •Limited to one lobe or less than 5 mets

Conclusions

• During the last decade has been significant improvements in the surgical treatment of gastrinoma that have had an impact

on its localization and survival

• Gastrinoma remains a challenging and interesting disease to treat by the surgeon