Zollinger-Ellison Syndrome Flashcards
What are the primary symptoms of Zollinger-Ellison syndrome (ZES)?
Severe peptic ulcer disease
chronic diarrhea
gastroesophageal reflux disease (GERD).
What causes Zollinger-Ellison syndrome?
Gastrin-secreting tumors
usually in the pancreas or duodenum
leading to overstimulation of acid-secreting parietal cells in the stomach
What are the two main treatment goals for ZES?
-Control of acid hypersecretion to manage refractory peptic disease
-control of the gastrinoma, which is often malignant.
How are the terms “gastrinoma” and “ZES” different?
“Gastrinoma” refers to the neuroendocrine tumor (NET) secreting gastrin
while “ZES” refers to the clinical manifestations of the disease
What percentage of ZES cases are associated with multiple endocrine neoplasia type 1 (MEN-1)?
20-25%
whereas nearly 50% of patients with MEN-1 will have gastrinomas.
What is the average time from symptom onset to ZES diagnosis, and why is there a delay?
About 8 years, often due to the widespread use of PPIs, which mask symptoms.
What is the current surgical treatment focus for ZES?
Resection of the gastrinoma and long-term pharmacologic acid suppression
What is the second most common functional neuroendocrine tumor after insulinoma?
Gastrinoma.
At what age is Zollinger-Ellison syndrome (ZES) usually diagnosed?
It is most commonly diagnosed in the fifth decade of life, typically between ages 20 and 60
At what average age do patients with MEN-1 typically develop ZES compared to sporadic cases?
The average age of onset for MEN-1 patients is 33.2 years, compared to 43.5 years for sporadic cases
With which other syndromes is gastrinoma sometimes associated?
von Hippel-Lindau syndrome
von Recklinghausen’s disease.
What normally controls gastric acid secretion to maintain pH homeostasis?
Negative feedback from somatostatin release by gastric D cells
What are the most common presenting symptoms of gastrinoma?
Abdominal pain and diarrhea (reported in over 70% of cases)
What is the average delay from symptom onset to ZES diagnosis
Between 6 and 8 years
Where are gastrinomas most commonly found?
In the pancreas or duodenum, specifically within the “gastrinoma triangle.”
What anatomical boundaries define the gastrinoma triangle?
The cystic duct, the second and third portions of the duodenum, and the neck and body of the pancreas.
In which ectopic locations can gastrinomas occasionally occur?
The stomach, bile duct, periportal lymph nodes, lungs, heart, and ovaries
What is the most common location for gastrinomas in the duodenum?
The first portion of the duodenum, with incidence decreasing distally.
Are duodenal gastrinomas easy to detect preoperatively?
No, they are often very small and can be difficult to identify preoperatively and intraoperatively.
What is the incidence of duodenal versus pancreatic gastrinomas in MEN-1 patients?
MEN-1 patients often have multiple tumors in the pancreas or duodenum
most sporadic gastrinomas occurring in the duodenum
What is the prognosis for patients with pancreatic gastrinomas versus duodenal gastrinomas?
Pancreatic gastrinomas have a poorer prognosis due to a higher rate of liver metastases
How do liver metastases affect the prognosis of gastrinoma patients?
Diffuse liver metastases are associated with a 10-15% 10-year survival rate, whereas absence of liver metastases corresponds to a 95% survival rate
What is the significance of the primary tumor size in gastrinomas?
Larger primary tumor size is predictive of distant metastasis
What is the typical Ki-67 proliferative rate in gastrinomas?
Gastrinomas have a low Ki-67 rate, around 1% to 2%, indicating they are generally slow-growing tumors.
How does the rate of lymph node metastasis compare between duodenal and pancreatic gastrinomas?
Duodenal gastrinomas have a higher rate of lymph node metastasis (70%) compared to pancreatic gastrinomas (40%)
When should a patient be referred for a ZES workup?
In cases of refractory peptic ulcer disease
long-standing diarrhea
ulcer disease without H. pylori infection
or failure to improve after H. pylori treatment and acid suppression therapy
What additional findings suggest MEN-1 in a patient being evaluated for ZES?
The presence of hypercalcemia or nephrolithiasis, which warrants screening for both gastrinoma and MEN-1.
What is the initial diagnostic test for ZES?
Measurement of fasting serum gastrin levels.
What conditions can cause hypergastrinemia other than ZES?
Pernicious anemia
atrophic gastritis
H. pylori infection
gastric outlet obstruction
antral G-cell hyperplasia
retained antrum
renal failure
short bowel syndrome
Why can pharmacologic acid suppression with PPIs complicate the diagnosis of ZES?
PPIs can cause achlorhydria, leading to hypergastrinemia due to the absence of acid-mediated suppression of gastrin secretion
What fasting serum gastrin level strongly suggests ZES if gastric pH is also low (<2)?
A fasting serum gastrin level greater than 1000 pg/mL.
What is basal acid output, and what are the thresholds indicating ZES?
Basal acid output has a sensitivity of 98% for ZES if it’s greater than 15 mEq/hour in unoperated patients
or greater than 5 mEq/hour in post-resection patients
How long should PPIs be discontinued before fasting serum gastrin testing?
At least 72 hours, ideally 7 days; H2 receptor antagonists can be used during this time to control symptoms
What provocative test is used to confirm ZES in patients with fasting hypergastrinemia?
The secretin stimulation test.
overnight fast
intravenous bolus secretin of 0.4 μg/ kg
Blood samples of gastrin levels at 0, 2, 5, 10, 20, and 30 minutes following secretin administration
not necessary to discontinue PPIs or H2 antagonists for this test.
What is the threshold for a positive secretin stimulation test?
An increase in gastrin of 110 pg/mL over baseline
What side effects may occur with intravenous secretin administration?
Mild side effects like nausea and flushing.
After confirming gastrinoma, what additional tests are performed to screen for MEN-1?
Measurements of ionized calcium, parathyroid hormone, prolactin, and pancreatic polypeptide levels.
What is the recommended initial treatment if MEN-1 and primary hyperparathyroidism are present?
Parathyroidectomy.
ZES Diagnosis Algorithm
Pic
What is the initial imaging modality for localizing a gastrinoma?
(CT) of the abdomen and pelvis, with fine cuts through the pancreas (pancreas protocol CT)
Which imaging technique may be more sensitive for detecting metastatic disease in ZES?
Magnetic resonance imaging (MRI).
Why are neuroendocrine tumors identifiable on imaging in the arterial and capillary phases?
They are hypervascular and show greater enhancement than normal pancreatic tissue during these phases
What is Somatostatin Receptor Scintigraphy (SRS) used for in ZES workup?
Preoperative localization of gastrinomas, using indium-labeled octreotide with affinity for type 2 somatostatin receptors
Which imaging method is replacing SRS for neuroendocrine tumors, including ZES?
68Ga-Dotatate PET/CT.
Why is 68Ga-Dotatate PET/CT preferred over OctreoScan?
It provides more accurate staging, higher detection rates for lesions, less radiation exposure, and quicker results.
Is standard 18F-fluorodeoxyglucose PET/CT recommended for evaluating gastrinomas?
No, due to the slow metabolic activity of gastrinomas, which makes them typically undetectable on FDG PET/CT.
What is the role of endoscopic ultrasound (EUS) in locating gastrinomas?
EUS is an invasive alternative for localization when other imaging is inconclusive, with high sensitivity and the ability to perform biopsies
What is the sensitivity of EUS for localizing small pancreatic neuroendocrine tumors (PNETs)?
Approximately 97%, compared to 85% for CT and 70% for MRI.
What is the purpose of a selective secretin stimulation test in ZES diagnosis?
To identify the blood supply of the tumor by measuring gastrin levels in the hepatic vein after intraarterial secretin injection
direct secretin injection into the hepatic, splenic, gastroduodenal, and superior mesenteric artery
Sampling At 0, 20, 40, and 60 seconds.
What imaging sequence is recommended for cost-effectiveness in localizing a gastrinoma?
Start with CT or MRI
followed by 68Ga-Dotatate PET
If negative, proceed to EUS, and if still negative, consider selective secretin testing.
What additional feature does 68Ga-Dotatate PET/CT offer compared to other imaging techniques?
It allows calculation of standardized uptake values, which helps in staging and assessing tumor burden.
How does surgical resection of sporadic gastrinomas impact liver metastasis?
Evidence suggests that resection decreases the rate of liver metastases
What specific techniques are used in surgery to locate duodenal gastrinomas?
Techniques include duodenotomy, mobilization of the duodenum, and in some cases, intraoperative transillumination
What recent findings support routine lymphadenectomy in sporadic ZES?
Lymphadenectomy with excision of over 10 lymph nodes is associated with a higher rate of biochemical cure and potentially prolonged disease-specific survival
What are the key prognostic factors for disease-specific survival in ZES?
Tumor size over 25 mm
Ki-67 index over 5%
preoperative gastrin level above 3000 pg/mL
and presence of liver metastases.
Why is exploration warranted in sporadic ZES patients with negative imaging?
Tumors in the duodenum, pancreas, or lymph nodes may be small and undetectable; an experienced surgeon can find a gastrinoma in 98% of such cases.
What surgical approach is recommended for hyperparathyroidism in MEN-1 patients?
A 3 ½ gland parathyroidectomy or total parathyroidectomy with autotransplantation, which can reduce baseline gastrin levels and medication needs.
How is the decision to resect gastrinomas in MEN-1 patients made?
Based on imaging: image-negative patients are observed,
while image-positive patients without metastasis may undergo local resection to improve survival.
What long-term outcomes are expected for MEN-1 patients with gastrinoma if aggressive resection is avoided?
MEN-1 patients can live up to 30 years without aggressive resection, with better quality of life compared to outcomes involving major pancreatic resections
What is the primary goal of surgery in Zollinger-Ellison syndrome (ZES)?
Tumor control, to reduce the risk of metastatic disease and potentially correct hypergastrinemia
What is the relationship between tumor size and metastasis in ZES?
Larger tumors, particularly pancreatic gastrinomas, are more likely to metastasize to the liver, even if they are small (< 2 cm)
What surgical approaches are preferred for ZES when feasible?
Enucleation or local resection for pancreatic head lesions,
and distal pancreatectomy for distal lesions
When is a Whipple resection considered in ZES treatment?
For large pancreatic head or duodenal lesions that cannot be removed by enucleation
What are the classifications of surgical resection in ZES?
R0: Complete excision with normal postoperative serum gastrin levels.
R1: Residual microscopic disease or complete excision with persistent hypergastrinemia.
R2: Gross residual disease with persistent hypergastrinemia.
What long-term benefit did Ellison demonstrate for patients with R0 or R1 resections?
Improved long-term survival compared to patients with R2 resections
What preoperative preparations are essential for ZES surgery?
Reviewing and confirming serum gastrin levels, secretin test results, imaging, and ensuring availability of special equipment like intraoperative ultrasound and an endoscope
PPI Pre op
NGT Placement
What is the typical surgical incision for open ZES surgery
midline or bilateral subcostal incision
When is laparoscopic surgery considered for ZES?
Only if preoperative imaging clearly localizes the tumor and enucleation is feasible
What are the initial steps upon opening the abdomen in ZES surgery?
Palpation of intraabdominal organs and “running” the small intestine to detect any secondary or ectopic tumors
What surgical maneuver aids in the examination of the pancreas during ZES surgery?
A wide Kocher maneuver facilitates bimanual palpation and better access to the pancreas, especially the head
How are tumors smaller than 2 cm in the pancreatic head and uncinate process typically managed?
Local excision is performed if the pancreatic duct is uninvolved, aided by intraoperative ultrasound and coagulation devices
What procedure is preferred for tumors located in the body and tail of the pancreas?
Distal pancreatectomy with splenectomy, especially since most gastrinomas are malignant
How are duodenal gastrinomas identified and removed?
A longitudinal duodenotomy allows internal palpation and excision, as these tumors are submucosal and do not usually require full duodenal resection.
What intraoperative tools can assist in locating small duodenal gastrinomas?
Intraoperative endoscopy
transillumination, and ultrasound, which are useful but only detect about 20-30% of these tumors externally
How is the duodenum closed after excision of a gastrinoma
Closure is performed longitudinally or transversely, depending on surgeon preference, using a single-layer technique.
How is PPI therapy managed postoperatively in ZES patients?
Initially continued intravenously, then switched to oral form once the patient can take liquids orally.
Why should PPI therapy be continued for 3 months postoperatively in ZES patients?
Hypergastrinemia induces parietal cell hyperplasia, which can take up to 3 months to resolve
When should a fasting gastrin level be measured postoperatively in ZES patients?
On day 3 after surgery and again at the first postoperative visit
What should be done if postoperative fasting gastrin levels are elevated?
Continue PPI therapy and repeat imaging 6 months after surgery.
What is the recommended course of action if imaging at 6 months shows positive results for gastrinoma?
Consider reexploration surgery.
Why are MEN-1 patients with extensive metastatic or locoregional disease typically not offered surgery
Because R2 resections do not improve survival in these patients
surgical resection of pNETs with vascular abutment/ invasion
is indicated
generally successful without requiring vascular reconstruction and should not be a contraindication to surgery
What is the effectiveness of liver resection for metastases in gastrinoma patients?
It is effective if the metastases are unilobar.
What are the primary goals of targeted liver therapy such as TACE or RFA in gastrinoma?
To directly damage liver metastases, primarily for nonsurgical candidates, though published data is limited.
What is the role of Everolimus in treating gastrinoma?
It is an mTOR inhibitor used as a second-line therapy after somatostatin analogues or liver-directed therapy.
What role do somatostatin analogues play in gastrinoma treatment?
They are first-line therapy for tumor control, with a 50% short-term response rate, though PPIs now largely manage acid reduction
