2. Robert Milton Zollinger
1903 - 1992
• Giant of american surgery
• “He was respected by his
peers, feared by his
students and loved by his
patients”
3. 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
4. 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
5. 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¨
6. Robert Milton Zollinger
Military
• Joined the army in 1941
• Commanded the 5th
general
hospital
• Legion of Merit Award
– Mobile surgical teams
• Battle Stars
– Normandy
– Northern France
– Rhineland
8. 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
14. • 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
18. Diarrhea
• Not typical for ulcer disease
• A prominent feature of Zollinger
Ellison syndrome
19. 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
20. Clues
• Diarrhea
• Ulcers in atypical locations
– Distal duodenum
– Jejunum
• H Pylori negative
• Failure of medical management
• Recurrent ulcers
• Hyperparathyroidism
21. 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
24. 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
25. 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%)
26. 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
diagnosis
CW Deveney. Annals of Internal Medicine 1977
H Frucht. Annals of Internal Medicine 1989
27. Tests for gastric hypersecretion
• Basal gastric output
– >15 mEq/h if no previous
surgery
• Maximal gastric outupt
• BAO/ MAO ratio
– > 0.6 = ZES
30. 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
31. 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%
32. Localization
Can be found anywhere in
the body
• CT
• MRI
• US
• Angiography
• Somatostation Receptor
Scintigraphy
33. Somatostatin Receptor Scintigraphy
“Ocreotide scan”
• Gastrinomas have
somatostatin receptors
• Radioactively labeled
ocreotide
• Single most sensitive study
• Misses small duodenal
gastrinomas
B Termanini. Gastroenterology 1997
35. 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
41. Duodenotomy
• Dr Norman Thompson
• University of Michigan
• The primary location for
gastrinomas is in the duodenum
• Imaging studies miss small
duodenal gastrinomas
43. Postoperative management
• Standard postoperative care
• At least 2 serum gastrin levels
• Secretin stimulation test
• Fasting serum gastrin and secretin stimulation test in 6
months
44. Metastases
• 60 – 85 % of gastrinomas are
malignant
• Hepatic metastases predicts
survival
• Localized liver metastasis should
be considered for surgery
45. 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
50. 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
51. Controversy 1
What 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)
52. Controversy 2
Should 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
53. 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
54. Controversy 4
Should 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
55. Controversy 5
What 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
56. 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
Editor's Notes
Good Morning, Thank you Dr Sirinek
Today I will give a presentation on the Zollinger Ellison Syndrome,
From Monterrey we go to Millersport, Ohio where Dr Robert Milton Zollinger was born.. Big Z, as he was called, was respected by his peers, feared by his residents and loved by his patients
He came from humble back ground. He was born on sept 4 1903 in Millersport ohio. and was raised in the farm where he attended a one room schoolhouse. He excelled in academics and graduated in medicine from the Ohio State University.
He started his internship at the Peter Bent Brigham hospital in Boston. And since at the time interns were not allowed to get married he waited for its conclusion to marry Louise Kiewet in 1929
After his internship he returned to Ohio to continue with his residency under Dr Elliot C Cutler whom he followed to Boston to become a Chief Resident. An amusing story comes from the first edition of the now well known atlas of surgical operations. It turns out that even though Zollinger did the majority of the work, it was Dr Cutler’s name which appeared first on the cover. When Zollinger asked Cutler whose name should appear first he answered that the names should be listed in alphabetic order
He did not hesitated when the time came to fight in the 2nd world war. He became a colonel and commanded the 5th general hospital . He developed mobile surgical teams and earned multiple battle stars
Then he returned to america and Ohio where he became a professor of surgery at the Ohio State University. He rose to chairman of the department within 1 year of his arrival .
In his long tenure as chairman, he made significant contributions to American surgery. Not only did he discovered the syndrome that bears his name, but also obtained multiple honorary degrees. He was the president of almost every surgical organization to which he belonged and was a recipient of the Sheen award which is the highest honorary title given by the American Medical Association. He was even offered the presidency of the Ohio State University, but he turned it down in order to continue active in academic surgery. However, those who knew him well, remark that one of his major achievements was: Training Dr. Sirinek.
Dr Zollinger will always be remembered as a surgeon with great qualities and one who helped shaped the surgery residency of our days. He was a perfectionist in everything he did and demanded nothing else from his residents. He was very competitive and a hard worker. He was caring to his patients. Ironically, Dr Zollinger died of pancreatic cancer in 1992, but his memory remains alive
Although the topic remains one of the most interesting and challenging diseases of all times, the management of patients with gastrinoma has changed considerably in the last decade. Today I´ll introduce you to these new concepts and discuss several resolved and unresolved controversies in the treatment of this syndrome.
The year was 1954 and the place was the department of surgery at the Ohio State University. It was the heyday of gastric surgery and Dr. Zollinger was doing over 5 gastrectomies per week. His partner, Dr Ellison had seen a patient who died of uncontrollable gastric hemorrhage and who in autopsy had an islet cell tumor of the pancreas. Dr Zollinger had just readmitted the first patient. She was a 26 year old female with recurrent duodenal ulcers despite vagotomy and pyloroplasty followed by a billroth 1 resection, then re’resection and gastric irradiation. She was taken to the OR for performance of a total gastrectomy and was found to have 2 small lymph nodes adjacent to the pancreas these were removed and sent with the specimen. The pathologist identified this tissue as islet cell tumors. That Saturday morning in grand rounds the syndrome was born.
Both Drs Zollinger and Ellison presented their findings at the meeting of the Southern Surgical Association in 1955. Their initial report sparked a significant interest of the surgical community for the syndrome. They described a clinical triad of benign jejunal ulcers, extreme acid hypersecretion and non B islet cell tumors of the pancreas
However, it was not until 5 years later that the peptide gastrin was isolated and later found cause the manifestations of the zollinger –ellison syndrome. Gastrin is produced in the G cells of the gastric antrum. Its main function is to cause the release of acid from the parietal cells in the stomach. A gastrin radioimmunoassay was not available until 1976 and then were the able to obtain serum gastrin values in a fast and reliable manner
Gastrinomas are tumors that are malignant in up to Âľ of the cases. Their incidence is 2 per million people but up to 1 /1000 in patients with duodenal ulcers. And 1 in 50 in patients with recurrent ulcer disease. It is usually sporadic but can also be a manifestation of the Multiple Endocrine Neoplasia type 1 syndrome
The management of gastrinoma depends on the identification of patients who may harbor the disease
The pĂ thophysiology of the zollinger ellison syndrome is depicted in this chart. Elevated gastrin secretion by the islet cell tumors causes the significantly increase in gastric acid by the stomach. This in turn causes ulcers and injury to the small bowel mucosa. The clinical manifestations are related to the symptomatology of ulcer related disease coupled with diarrhea and malabsorption from small bowel mucosal injury
This can manifest with the typical symptoms of ulcer disease or with malabsorption related to small bowel mucosal injury
Diarrhea is distinctive feature not typically present in patients with garden variety ulcer disease but found in a large proportion of patients with gastrinoma .
It is relatively common for patients to be misdiagnosed in one or more occasions. Multiple other pathologies can be confused with the syndrome such as:….. Thus, a high index of suspicion is required to make the diagnosis
So nowadays, one should be suspicious of gastrinoma in patients with ulcers and on or more of the following clues:…..
Admittedly, the introduction of h2 receptor blockers and proton pump inhibitors has made harder to diagnose gastrinoma and to obtain adequate cure rates. We are now seeing more patients with advance disease and are achieving lower 5 year survival rates
This table outlines the experience from Ohio state in patients with gastrinoma in 4 eras. Upon discovery, second decade, after the introduction of a gastrin radioimmunoassay and after the introduction of antacid medications. Note how the percentage of patients presenting with metastatic disease increased significantly in the last era and how this was coupled with dramatic reductions in the 5 year survival for this patients
The diagnosis of ZE syndrome centers in the objective documentation of hypergastrinemia along with increased gastric acid secretion.
It is important to document the presence of gastric acid hypersecretion, since many other etiologies can cause hypergastrinemia, such as:…. Serum gastrin levels can be elevated by the use of acid suppressing medications as achloridria triggers hypergastrinemia
The introduction of the gastrin Radioimmunoassay in 1976 revolutionized the diagnosis of gastrinoma. It was now simple and accurate to objectively document hypergastrinemia. A normal gastrin level is below 200 pg/ml and a level greater than 1000 pg /ml is diagnostic for gastrinoma. However the majority of patients with ZE syndrome have gastrin values of less than 1000 and confirmatory tests are needed to make the diagnosis
In these patients, the secretin stimulation test is used as a confirmation of the syndrome. Secretin is used since studies have found that this hormone increases gastrin secretion in patients with gastrinoma while it does the opposite in normal patients. A dose of 2 units per kg of intravenous secretin is administered and gastrin values are measured at serial intervals. A rise in the gastrin levels of greater than 200 pg /ml confirms the diagnosis
In order to objectively document gastric acid hypersecretion, both the basal or the maximal gastric acid output can be measured. A basal gastric acid output of greater than 15 mEq /l or a Basal over maximal acid output ratio of greater than 0.6 constitute gastric acid hypersecretion
These are 3 of the major hospitals in Monterrey. On the top left is the University Hospital, which provides specialized care for the poor as well as training in a broad range of specialties. In the Middle is the Christus Muguerza Hospital, which has a long history of being a renowned private institution. An on the bottom right is the Hospital San Jose, which is a mixed academic and private practice hospital
Once diagnosis has been determined clinically. The next step is to localize the tumor by either radiological or surgical means in order to allow for tumor removal.
Over 80 % of these tumor are found in the so called gastrinoma triangle. This area is formed by tracing a line between the junction of the cystic and common bile ducts, the junction between the 2nd and 3rd portions of the duodenum and the junction of the neck and the body of the pancreas.
Although in the first cases, the gastrinomas were identified in the pancreas, it is now well known that duodenal gastrinomas are much more common than pancreatic tumors. In an NIH sponsored study of 123 patients, duodenal gastrinomas were identified in 47 % compared to 14 % for pancreatic. Another 13 % where identified in lymph nodes and 9 % in other locations all over the body such as the liver, bile duct, stomach, spleen, mesentery and ovary
Since gastrinomas can be found all over the body, preoperative localization is ideal. Several radiological modalities have been used each with its attributes and limitations. CT and MRI are good in surveying the whole abdominal cavity and for identifying the presence of liver metastases. Ultrasound is particularly helpful intraoperatively and arteriography has been used for selective secretin infusion tests
The somatostatin receptor scintigraphy, also known as the ocreotide scan takes advantage of the fact that gastrinomas have somatostatin receptors in their cell surface and that radioactively labeled ocreotide can bind to these receptors. It gives full body imaging and although it can miss some small duodenal gastrinoma it constitutes the single most sensitive study for localization of primary tumors.
This graph taken from a study by Norton and colleagues shows the sensitivity for detection of primary tumors of the several imaging modalities. Note how SRS is the single most sensitive study and that together with CT scan, one can detect up to 70 % of the gastrinomas preoperatively. Somatostatin receptor scintigraphy should constitute the initial imaging modality for gastrinomas
In the remaining 30% of the patients with gastrinoma, the tumor would not be able to be localized preoperatively and it would need to be done intraoperatively. By performance of a diligent and systematic abdominal exploration the surgeon will be able to localize all but 10 % of the gastrinomas.
The operation can be done through either a midline or a bilateral subcostal incision. The entire abdominal cavity should be carefully inspected for any evidence of metastatic disease. Any suspicious tissue should be removed and sent for frozen section examination. Particular attention should be paid to the liver which is the most common site for metastases. Intraoperative ultrasound of the liver is an important consideration. After an extensive kocher maneuver the pancreas should be carefully palpated for any masses. Intraoperative ultrasonography of the pancreas is also helpful. In order to detect small duodenal tumors, an anterolateral duodenotomy with mucosal palpation should be performed. All peripancreatic and periduodenal lymph nodes should be removed and sent for frozen section analysis. With these maneuvers the surgeon will be able to successfully identify and treat the majority of patients with gastrinoma.
Ok. So now that we have identified the sneaky gastrinoma. What are we to do with it?
Current recommendations call for tumor resection with negative margins and adherence to oncologic principles. For small pancreatic and duodenal gastrinomas, simple tumor enucleation would do, yet larger tumors may require a pancreaticoduodenectomy or a or distal pancreatectomy. A total gastrectomy was done initially to control gastric acid hypersecretion yet it is no longer required.
Up until recently, there remained a significant amount of controversy as to whether surgical intervention impacted survival. But this study from Dr Norton conclusively demonstrated that tumor removal significantly impacts both overall survival and disease related survival. On it, patients with ZE syndrome who underwent resection were compared with non-resected patients and were followed long term . The study shows statistically significant differences in overall survival and disease free survival .
Not long ago, gastrinomas were still considered to be found predominantly in the pancreas and there were large number of patients in whom the tumor could not be found. As mentioned previously, imaging studies do poorly in localizing small duodenal tumors. The introduction of an anterolateral duodenotomy and duodenal palpation has represented a significant breakthrough in the diagnosis of gastrinoma
Here, it is shown how the routine performance of a duodenotomy significantly influences the detection rate for gastrinomas and thus it impacts the biochemical cure rates. It does not impact the development of liver metastases or the overall survival
Following the operation and standard postoperative care, it is important to document a biochemical cure and reaffirm complete tumor removal . This information can be obtained from a follow up secretin stimulation test
As I mentioned previously, gastrinomas represent a low grade malignancy and as such it can be associated with metastatic disease. Metastasis occur preferentially in the liver and thus constitute the most important predictor of long term survival. Liver metastatectomy should be considered in a select group of patients
In this study, the effect of liver metastasis on survival is highlighted. Patients without metastatic diseas enjoyed a 95 % 10 year survival whereas those with diffuse liver involvement had uniformly fatal outcomes. Note the subset of patients with localized metastasis for whom surgical intervention can be offered
Newer data suggests that selected patients with hepatic metastases from neuroendocrine tumors obtain a survival advantage from surgical resection
Liver metastatectomy in neuroendocrine tumors has also been shown to positively impact survival in selected patients
Just like any other cancer, the prognosis is dependent on the extent of disease, the biologic characteristics of the cancer and the therapy provided
Recently, we reached the 50 year anniversary of the discovery of the Zollinger Ellison syndrome. Even though we have surpassed incredible challenges, many more still remain. This is evidenced by the still poor long term survival of patients with metastatic gastrinoma. The adjoining graph demostrates the long term survival at Ohio state in patients with the syndrome.