the withholding of exogenous glucose). During a monitored fast, blood is sampled for glucose and

insulin determinations every 4 to 6 hours and when symptoms appear. Hypoglycemic symptoms

typically occur when glucose levels are below 50 mg/dL, with concurrent serum insulin levels often

exceeding 25 microunits/mL. Additional support for the diagnosis of insulinoma comes from the

calculation of the insulin-to-glucose ratio at different times during the monitored fast. Normal persons

have insulin-to-glucose ratios below 0.3, whereas patients with insulinoma typically demonstrate

insulin-to-glucose ratios above 0.4 after a prolonged fast. Other measurable β-cell products synthesized

in excess in patients with insulinoma include C peptide and proinsulin. Elevated levels of both are

typically found in the peripheral blood of patients with insulinoma.

The possibility of the surreptitious administration of insulin or oral hypoglycemic agents should be

considered in all patients with suspected insulinoma. Levels of C peptide and proinsulin are not elevated

in patients who self-administer insulin. Additionally, patients self-administering either bovine or porcine

insulin may demonstrate anti-insulin antibodies in circulating blood. The ingestion of oral hypoglycemic

agents, such as sulfonylureas, can be assessed by means of standard toxicologic screening.

7 Insulinomas are evenly distributed throughout the pancreas, with one-third found in the head and

uncinate process, one-third in the body, and one-third in the tail of the gland.85 Less than 3% are located

outside the pancreas, with these lesions located in the peripancreatic area.86 Ninety percent are found to

be benign solitary adenomas amenable to surgical cure. Ninety percent of insulinomas are sporadic,

with approximately 10% being associated with the MEN-1 syndrome. In patients with MEN-1, the

possibility of multiple insulinomas must be considered, and recurrence rates are higher. In

approximately 10% of patients, insulinoma is metastatic to the peripancreatic lymph nodes or liver,

making the diagnosis of malignant insulinoma.

Figure 56-6. The technique for enucleating a benign pancreatic endocrine neoplasm with scissors (A) or electrocautery (B). C:

After enucleation, the site of excision is drained.

After the diagnosis of insulinoma has been confirmed biochemically, the appropriate localization and

staging studies described earlier are performed (typically CT and EUS). Once the lesion has been

localized,87 patients undergo surgical exploration, where the pancreas is assessed not only by operative

palpation but also by intraoperative ultrasonography. This allows for confirmation of preoperative

localization and evaluates for the presence or absence of multiple primary tumors. Small, benign tumors

that are not close to the main pancreatic duct can be removed by enucleation88 (Fig. 56-6), regardless of

their location in the gland. Larger tumors in the neck or proximal body may be resected via central

pancreatectomy.89–91 In the body and tail of the pancreas, insulinomas more than 2 cm in diameter and

those close to the pancreatic duct are most commonly removed via distal pancreatectomy. Large lesions

in the head or uncinate process of the gland may not be amenable to local resection and may

occasionally require pancreaticoduodenectomy for complete excision.92,93 Increasingly, experienced

surgeons are utilizing a laparoscopic approach to these tumors. Both laparoscopic pancreatectomy and

1435

enucleation are now performed on a routine basis with excellent results.94–98

In rare instances, preoperative localization studies and intraoperative ultrasound fail to identify the

tumor. Intraoperative biopsy of the pancreatic tail may help make the diagnosis of nesidioblastosis as

the cause of hyperinsulism. Some authors have recommended a “blind” distal pancreatic resection to the

level of the superior mesenteric vein (60% to 70% pancreatectomy), in the hope of excising an

unidentified insulinoma in the body and tail. Others have suggested blind pancreaticoduodenectomy,

because the thickness of the gland in this region makes it more likely to harbor an occult neoplasm. The

favored approach at the current time is to defer any blind resection, close the patient without

pancreatectomy, and perform postoperative selective arterial calcium stimulation with hepatic venous

insulin sampling to allow for specific tumor localization and directed surgical excision at a second

operation.99

Approximately 10% of insulinomas are malignant, presenting with lymph node or liver metastases. In

the presence of hepatic metastases, resection of the primary tumor and accessible metastases should be

considered if it can be performed safely.100–102 Such tumor debulking can be helpful in reducing

hypoglycemic symptoms and improving long-term survival. In patients with unresectable disease,

medications such as diazoxide and octreotide can be used to reduce insulin secretion from the tumor,

minimizing hypoglycemia. One promising new treatment is everolimus, an oral rapamycin analog that

inhibits mammalian target of rapamycin (mTOR). In a pilot study of patients with refractory

hypoglycemia due to metastatic insulinoma, everolimus resulted in improved glycemic control.103

Dietary manipulations, including judicious spacing of carbohydrate-rich meals and the consumption of

nighttime snacks, can also reduce the number of hypoglycemic episodes. Multiple chemotherapeutic

regimens have been used including streptozocin, dacarbazine, doxorubicin, and 5-fluorouracil.104–106

Combination chemotherapy has yielded the highest response rates but has not been shown to be

curative.

GASTRINOMA (ZOLLINGER–ELLISON SYNDROME)

8 In 1955, Zollinger and Ellison described two patients with severe peptic ulcer disease and pancreatic

endocrine tumors and postulated that an ulcerogenic agent originated from the pancreatic tumor.107–109

It has been estimated that approximately 1 in 1,000 patients with primary duodenal ulcer disease and 2

in 100 patients with recurrent ulcer after ulcer surgery harbor gastrinomas.110 Seventy-five percent of

gastrinomas occur sporadically, and 25% are associated with the MEN-1 syndrome. Historically, the

majority of gastrinomas were found to be malignant, with metastatic disease present at the time of

initial workup. With increased awareness and screening for hypergastrinemia, the diagnosis of

gastrinoma is made earlier and a higher percentage of patients present with benign and potentially

curable neoplasms.111

Table 56-6 Gastrinoma

The clinical symptoms of patients with gastrinoma are a direct result of increased levels of circulating

gastrin (Table 56-6). Abdominal pain and peptic ulceration of the upper gastrointestinal (UGI) tract are

seen in up to 90% of patients. Diarrhea is seen in 50% of patients, with 10% having diarrhea as their

only symptom. Esophageal symptoms or endoscopic abnormalities resulting from gastroesophageal

reflux are seen in up to half of patients. The diagnosis of gastrinoma should be suspected in several

clinical settings, including the initial diagnosis of peptic ulcer disease, recurrent ulcer after medical or

surgical therapy, postbulbar ulcer, family history of ulcer disease, ulcer with diarrhea, prolonged

undiagnosed diarrhea, MEN-1 kindred, nongastrinoma pancreatic endocrine tumors (high association of

secondary hormone elevations), and prominent gastric rugal folds on UGI examination. Serum gastrin

1436

levels should be obtained in all of these settings.

In most patients with gastrinoma, the fasting serum gastrin level is greater than 200 pg/mL. Gastrin

levels greater than 1,000 pg/mL in the setting of documented hyperacidity and ulcer disease are

virtually pathognomonic for gastrinoma. Because hypergastrinemia can occur in other pathophysiologic

states (Table 56-7), fasting hypergastrinemia alone is not sufficient for the diagnosis of gastrinoma.

Gastric acid analysis (or at least gastric pH testing) is critical in differentiating between ulcerogenic

(high levels of acid) and nonulcerogenic (low levels of acid) causes of hypergastrinemia. To obtain an

accurate gastric acid analysis, patients must not be taking antisecretory medications including histamine

(H2

)-receptor antagonists or proton pump inhibitors (PPIs). The diagnosis of gastrinoma is supported by

a basal acid output above 15 mEq/hr in nonoperated patients, a basal acid output exceeding 5 mEq/hr

in patients with previous vagotomy or ulcer operations, or a ratio of basal acid output to maximal acid

output exceeding 0.6.

Table 56-7 Disease States Associated With Hypergastrinemia

Figure 56-7. Results of intravenous secretin stimulation tests in patients with atrophic gastritis (triangles), gastric outlet obstruction

(squares), and gastrinoma (circles). A positive test result, consistent with the presence of gastrinoma, is indicated by an increase

over basal serum gastrin levels of at least 200 pg/mL. (Adapted from Wolfe MM, Jensen RT. Zollinger-Ellison syndrome: current

concepts in diagnosis and management. N Engl J Med 1987;317:1200–1209.)

After documenting that hypergastrinemia and excessive acid secretion exist, provocative testing with

secretin should be performed to differentiate between gastrinoma, antral G-cell hyperplasia or

hyperfunction, and the other causes of ulcerogenic hypergastrinemia. This is achieved with a secretin

stimulation test (Fig. 56-7). A baseline gastrin level is drawn. The patient is then stimulated with 2

units/kg of secretin as an intravenous bolus and subsequent gastrin samples are collected at 5-minute

intervals for 30 minutes. An increase in the gastrin level by more than 200 pg/mL above the basal level

supports the diagnosis of gastrinoma.

After the biochemical diagnosis of gastrinoma has been made, the gastric acid hypersecretion should

be pharmacologically controlled. The PPIs are now considered the drugs of choice for doing so.112,113

The dose is adjusted to achieve a nonacidic pH during the hour immediately before the next dose of the

drug. Typically, PPI doses needed for acid control exceed usual dosing levels. After the initiation of

antisecretory therapy, all patients should undergo imaging studies to localize the primary tumor and to

assess for metastatic disease.

If localization studies reveal unresectable hepatic metastases, the patient should undergo

percutaneous or laparoscopic-directed liver biopsy to obtain a definitive histologic diagnosis. These

patients should be maintained on long-term PPI therapy. Virtually all patients can be rendered

achlorhydric with an appropriate dose of PPIs. Patients noncompliant with antisecretory therapy who

experience complications related to their ulcer diathesis may require removal of the end organ (total

1437

gastrectomy) if tumor resection is not possible. However, total gastrectomy, once the operation of

choice for gastrinoma, is now only rarely used.

9 If unresectable disease is not identified by staging studies, patients should be offered surgical

exploration with curative intent. On exploration, the entire abdomen should be assessed for areas of

extrapancreatic and extraduodenal gastrinomas. Most gastrinomas are found in the gastrinoma

triangle85,114 (Fig. 56-8), the area to the right of the superior mesenteric vessels, in the head of the

pancreas or in the duodenal wall. Both intraoperative ultrasound and intraoperative upper endoscopy

may be helpful in tumor localization. Transillumination of the duodenum may help identify small

duodenal gastrinomas.115,116 Well-encapsulated tumors less than 2 cm in size and distant from the

pancreatic duct can be enucleated. Those situated deep in the parenchyma may require partial resection

by pancreaticoduodenectomy or distal pancreatectomy. If no pancreatic tumor is identified, a

longitudinal duodenotomy should be performed at the level of the second portion of the duodenum in

search of duodenal microgastrinomas.117,118 Small gastrinomas in the duodenal wall can be locally

resected with primary closure of the duodenal defect. The routine use of duodenotomy increases the

short- and long-term cure rates in patients with sporadic gastrinoma, because such a duodenotomy

allows detection of more duodenal gastrinomas.119 Duodenotomy did not impact the occurrence of

hepatic metastases or disease-related mortality. In a small percentage of patients, gastrinoma is found

only in peripancreatic lymph nodes, with these lymph nodes harboring the apparent primary tumor.

Resection of these apparent lymph node primary gastrinomas has been associated with long-term

eugastrinemia and biochemical cure in up to half of cases.120 A review from the National Institutes of

Health identified likely primary lymph node gastrinomas in 26 of 176 gastrinoma patients (14.7%),

with 69% being eugastrinemic at a mean of 10 years after resection.121

Figure 56-8. Most gastrinomas are found within the gastrinoma triangle.

Occasionally, preoperative localization studies may identify the tumor in the gastrinoma triangle, but

at the time of exploration, the tumor is not demonstrable. Several surgical options are available at this

point. First, a parietal cell vagotomy has been proposed as a way to reduce antisecretory drug dose

requirements in patients on high-dose antisecretory drug therapy but without prior life-threatening

complications.122 However, this approach leaves behind potentially resectable gastrinoma and has lost

favor as an option. A second option is total gastrectomy; however, the availability of PPIs has

drastically reduced the need to perform this operation for gastrinoma. It may have a limited role in

patients whose tumors cannot be localized, if they cannot or will not take their PPIs. Like parietal cell

vagotomy, this leaves tumor behind. A third, controversial option in patients with localization to the

gastrinoma triangle is blind pancreaticoduodenectomy. Some argue this should include distal

gastrectomy, as duodenal gastrinomas may arise close to the pylorus and be left behind during a

pylorus-preserving resection.

Patients with sporadic gastrinomas tend to fare better following resection than those with MEN-1. In

a series of 151 patients reported by Norton et al.,123 123 had sporadic gastrinoma and 28 had MEN-1–

associated gastrinoma. Of those with sporadic gastrinoma, 34% were free of disease 10 years following

resection. None of the MEN-1 patients were free of disease at 10 years. A more recent review of 195

patients from the same institution demonstrated clear superiority of surgical intervention over other

treatment strategies.124 The rate of disease-related death was increased 23-fold in the group of patients

1438