Zollinger-Ellison Syndrome (Gastrinoma)

Kunwardeep Sohal, PGY2 Sept 30, 2008

Pathology

Derived from multipotential stem cells of endodermal origin. Known as enteroendocrine cells, they arise mainly in the pancreas as well as the small intestine Affinity for chromium and silver salts, which are useful markers for the histopathologist As many as 70 percent of gastrinomas form in the duodenum; the remainder, with rare exception, arise in the pancreas or less often (approximately 5 percent) in lymph nodes adjacent to the pancreas Duodenal gastrinomas tend to be quite small and are often multiple; they have less malignant potential than the solitary, sporadic pancreatic gastrinomas

Gastrins Function
Gastrin

has trophic action on parietal cells and histamine-secreting enterochromaffinlike (ECL) cells Gastrin stimulates parietal cells largely via the release of histamine

Clinical Manifestations
90

percent of patients with the Zollinger-Ellison syndrome develop peptic ulcers Diarrhea can also be a prominent feature of ZES (high rate of gastric acid secretion, resulting in a volume load that cannot be fully reabsorbed by the small intestine and colon)
Pancreatic

bicarbonate secretion is inactivated by the acidic volume load, no emulsification of fat

Heartburn

and weight loss were reported by 44 and 17 percent of patients, respectively, and initial presentation was with gastrointestinal bleeding in 25 percent

Diagnosis

There have been three for the diagnosis of Zollinger Ellison syndrome: Fasting serum gastrin concentration (upper limit of normal for serum gastrin is 110 pg/mL) Secretin stimulation test Gastric acid secretion studies Only the fasting serum gastrin concentration and the secretin stimulation test are used routinely However, about two-thirds of patients with the ZollingerEllison syndrome have serum gastrin concentrations less than 10 times the upper limit of normal (generally between 150 and 1000 pg/mL Can appear as part of MEN1parathyroid, pituitary, pancreas

Contd
Serum

chromogranin A is a general marker for neuroendocrine tumors that does not differentiate between the various subtypes of tumors. Nevertheless, it is elevated in most patients with gastrinomas, and the level of elevation correlates with tumor volume (normal or near normal in pernicious anemia patients)

Localization of tumor
Two

predominant methods:

Somatostatin

receptor imaging with 111Indium-penetreotide (Octreoscan) and SPECT, which has a higher sensitivity than all other imaging modalities, and is particularly useful in identifying liver and bone metastases Endoscopic ultrasound is especially valuable in imaging small pancreatic endocrine tumors, and permits fine needle aspiration for histological identification.

Treatment
GOAL:

limit the clinical manifestations and complications of peptic ulcer disease Usually, gastroenterologists to initiate and maintain proton pump inhibitors at high dosage (eg, 60 mg/day of omeprazole), using symptoms alone as a signal to increase the dose **PPIs irreversibly binding to and inhibiting the hydrogen/potassium ATPase that resides on the luminal surface of the parietal cell

Surgery

Sporadic gastrinoma who do not have evidence of metastatic spread of disease should be offered exploratory laparotomy and resection with curative intent (prevention of spread, up to 50% cure rate) 80% of curable gastrinomas lie within the gastrinoma triangle comprised of the head of the pancreas and the duodenal sweep (porta hepatis/transverse fissure of liver is apex of triangle)

Surgery, contd
Parietal

cell vagotomy performed at the time of tumor resection has been advocated to reduce the need for postoperative medical therapy, though not done often given efficacy of PPIs Prospective study of 124 patients with gastrinoma: 3% of the 98 patients who underwent resection developed liver metastases during a mean follow-up period of 6.3 years
23

percent of 26 patients treated medically developed metastatic disease over a slightly longer follow-up period (8.7 years)

Metastatic Disease
Most

common site, LIVER, and 2nd most common is bone (7%) Unfortunately, current treatment modalities are of limited benefit Other options:
Octreotide

can reduce gastrin levels, and may slow tumor growth

True radiologic response rate is probably between 10 and 40 percent

Surgery in metastatic disease

Hepatic

resection is indicated for the treatment of metastatic liver disease in the absence of diffuse bilobar involvement (rarely curative, prolonged survival is goal given slow growing nature of tumor) Should be considered only for patients with a limited number of hepatic metastases

Embolization

Liver metastases derive most of their blood supply from the hepatic artery, whereas healthy hepatocytes derive about 70 percent of their blood supply from the portal vein. This provides the rationale for therapeutic embolization of the hepatic artery, with the goal of inducing necrosis of the metastases with minimal damage to normal liver parenchyma

Prognosis

185 patients with ZES were followed prospectively for a mean of 12.5 years Liver metastases were found in 24 percent of patients at the time of diagnosis; the majority of these patients had a primary pancreatic neoplasm, and 67 percent had primary tumors that were greater than 3 cm in size Patients with liver metastases had a 10-year survival of only 30 percent compared to a 15-year survival of 83 percent in those without liver metastases Patients with liver metastases had a 10-year survival of only 30 percent compared to a 15-year survival of 83 percent in those without liver metastases. Fasting serum gastrin levels: The five-year survival rates for patients with mild (0 to 499 pg/mL), moderate (500 to 1000 pg/mL), or severe elevations (>1000 pg/mL) of FSG were 94, 92, and 86 percent