The Zollinger-Ellison Syndrome A Collective Surgical Experience

DAVID R. FARLEY, M.D.,* JON A. VAN HEERDEN, M.B., CH.B., F.A.C.S., F.R.C.S.(EDIN)(HoN),* CLIVE S. GRANT, M.D., F.A.C.S.,* LAURENCE J. MILLER, M.D.,t and DUANE M. ILSTRUP, M.S.4

A retrospective study of 90 surgically treated patients with the Zollinger-Ellison syndrome seen from 1958 through 1990 was performed. Fifteen patients had Zollinger-Ellison syndrome as a manifestation of multiple endocrine neoplasia type I. Preoperative tumor localization was positive in 46% of 54 patients studied. Gastrinomas were identified in 66% of patients, 38% of the tumors being malignant. Postoperative eugastrinemia was achieved in 11% of patients after a variety of surgical procedures. Exploratory laparotomy provides the only chance for cure and identifies the significant prognostic factors associated with longterm patient survival: small tumor size, extrapancreatic primary, and absence of tumor metastases.

A LTHOUGH DOCTORS ZOLLINGER and Ellison uncovered the mystery of hypergastrinemia with their epoch publication in 1955, which recommended total gastrectomy for effective therapy,' multiple improvements in radiographic imaging, pharmacologic therapy, and surgical techniques in the ensuing three decades have made the current treatment of patients with Zollinger-Ellison syndrome (ZES) controversial. Historically, it was believed that tumor excision for cure was possible in only 2% to 5% of patients.24 Understandably, with the introduction of pharmacologic agents that essentially shut off gastric acid secretion (histamine-receptor [H2] blockade in 1976 and blockage of the H+-K+ adenosine triphosphatase pump with omeprazole in 1984), some authorities recommended medical therapy in place of surgical treatment for patients with ZES.3 Coupling the initial development (1968)5 and subsequent improved accuracy of gastrin radioimmunoassay with a heightened physician awareness of ZES, patients are currently seen earlier in the course of their disease.

Presented at the 103rd Annual Scientific Session of the Southern Surgical Association Hot Springs, Virginia, December 1-5, 1991. Address correspondence and reprint requests to Jon van Heerden, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905. Accepted for publication December 30, 1991.

561

From the Department of Surgery, * the Division of Gastroenterology and Internal Medicine,t and the Section of Biostatistics Mayo Clinic and Mayo Foundation,f Rochester, Minnesota

Development of potent antisecretory agents increased the enthusiasm for resection of tumor with the aim of achieving permanent cure and avoiding lifelong drug therapy with its associated costs and possible side effects (Table 1). Currently, careful search and removal of gastrinomas has yielded putative cure rates in 30% to 53% of selected patients.68 The present study was undertaken to assess our expe-

rience with the changing surgical and pharmacologic management of patients with ZES and to delineate factors significant for long-term survival.

Patients and Methods Of 156 patients with well-characterized ZES seen at the Mayo Clinic from 1958 through 1990, 90 patients undergoing surgical exploration form the basis of this retrospective report. Sixty-six patients were excluded from this study because of nonoperative management: 33 with extensive hepatic metastases were deemed unresectable, 20 refused operative management, 9 with the multiple endocrine neoplasia type I (MEN-I) syndrome and asymptomatic on medication had multicentric pancreatic involvement and thus operative therapy was deferred, 2 were refused operation because of prohibitive anesthetic risk, and 2 asymptomatic patients with MEN-I syndrome were believed not to be candidates for operation at that time. Factual data of the 90 surgical patients was obtained regarding presenting symptomatology, diagnostic and laboratory evaluation, operative intervention, postoperative morbidity and mortality rates, pharmacologic ther-

FARLEY AND OTHERS

562

Ann. Surg. * June 1992

TABLE 1. Cost of Pharmacologic Control of Zollinger-Ellison Syndrome Drug

Cimetidine Ranitidine Famotidine Omeprazole *

Average Effective Daily Dose (mg)*

3600 1200 250 80-90

TABLE 2. Presenting Symptoms

Symptom Yearly Costt

No. of Patients (%)

Epigastric pain

84 (93) 46 (51) 2 (2) 1 (1) I (1)

Diarrhea $3714.12 $2514.36 $5714.59 $5008.42

Dizziness

Weight loss Abdominal mass

Data from Maton et al. Gastroenterol Clin North Am 1989.

t Calculated wholesale cost ordering bulk amounts to Mayo Pharmacy

in 1991.

omeprazole (4%), somatostatin (2%), or streptozotocin (1%). Only 14 patients (16%) were not taking medication.

apy, and long-term follow-up. Current survivors were contacted by telephone or were seen for physical examination within the past year (through January of 1991). The diagnosis of ZES was confirmed in each patient based on at least two of the following criteria:

Laboratory Analysis Preoperative gastric acid analysis (n = 15) disclosed a mean basal acid output of 40.2 mmol HCl/hour (range, 11.0 to 90.0). The average pH of a preoperative gastric aspirate was 1.29 (range, 0.9 to 2.4). Before abdominal exploration, baseline serum gastrin values ranged from 140 to 21,000 pg/mL (mean, 2357 pg/mL; Mayo normal range, 0 to 200 pg/mL). Of 31 patients tested by secretin stimulation, including two patients

1. History of severe peptic ulcer disease or unexplained diarrhea 2. Fasting serum hypergastrinemia (>200 pg/mL) or markedly elevated gastric acid output (> 15 mmol HCI/ hour) 3. Positive secretin-stimulated gastrin analysis (increase in serum gastrin of > 200 pg/mL after intravenous injection of 2 units secretin/kilogram of body weight) 4. Histologic confirmation of a neuroendocrine tumor

Analysis of discrete and continuous variables was performed using the log rank test9 and Cox's proportional hazards model,'0 respectively. Estimates of survival for the study group and an age- and sex-matched control population (1980 North Central United States) were compared using the method of Kaplan and Meier. ' Multivariate associations of survival were investigated using the model of Cox.'0 Results

Epidemiology Surgical exploration was performed in 59 men and 31 women. Operative candidates ranged in age from 13 to 72 years (mean, 51 years). Sporadic disease occurred in 75 patients (83%), whereas 15 patients (17%) had hypergastrinemia as a manifestation of the MEN-I syndrome.

with normal baseline levels, all had serum gastrin elevations of >200 pg/mL within 20 minutes after injection.

Preoperative Radiographic/Endoscopic Evaluation Upper gastrointestinal barium radiography or esophagogastroduodenoscopy delineated extensive peptic ulceration in 91% of patients. Since the advent of H2 receptor blockade, less than 70% of patients have evidence of peptic ulceration, and even then, ulceration is minimal, with only minor mucosal changes. Duodenal ulceration was detected in 63 patients, jejunal ulceration in 9, and 10 patients had peptic ulceration in both locations. Eight patients had no evidence of peptic ulceration. Fifty-four patients underwent further evaluation to attempt to identify the location of the primary tumor or evidence of metastasis. Preoperative localization of the primary gastrinoma was successful in only 25 of these 54 patients (46%) (Table 3). TABLE 3. Diagnostic Imaging of Gastrinomas in Patients With Zollinger-Ellison Syndrome

Primary Identified No. of Patients

Symptoms

Patients presented with an array of physical complaints (Table 2) at the time of diagnosis, with a median duration of symptoms of 2 years (mean, 3.2 years; range, 2 months to 18 years). On presentation to the Mayo Clinic, most patients were on pharmacologic therapy for peptic ulcer disease or diarrhea: antacids (49%), H2 antagonists (28%),

Computed tomography Angiography Preoperative ultrasonography Magnetic resonance imaging

Intraoperative ultrasonography

40 20 19 11 10

54

No. (%)

13 (33) 1 (5) 7 (36) 4 (36) 6 (60) 31 (57)

Metastasis Identified 7 2

0 4 1

14

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SURGICAL TREATMENT OF THE ZOLLINGER-ELLISON SYNDROME 0-0.9 cm

Surgical identification, or confirmation by palpation, of the primary gastrinoma occurred in 53 patients (59%). The use of intraoperative ultrasonography imaged nonpalpable tumors in six additional patients (7%). Thus, of the 90 patients, primary tumor wasfirst identified by preoperative imaging in 25 (28%), by intraoperative palpation in 28 (31%), and by intraoperative ultrasonography in 6 (7%). A primary tumor was, therefore, not identified in 31 patients (34%), although 7 such patients had identifiable metastatic disease (lymph nodes 5, liver 2). Thus, in 24 patients (27%), most of whom were operated on long before thorough duodenal evaluation was standard procedure, the potentially curable gastrinoma was never identified. Pathology

Primary gastrinomas were identified pathologically in 59 patients (66%) (Table 4). Fifty such tumors were located within the gastrinoma triangle, including 13 duodenal tumors (Fig. 1). Tumor size ranged from 0.2 to 12 cm in largest diameter (mean, 3.1 cm; median, 2.5 cm). Metastatic involvement was documented in 34 patients (38%). A single patient was found to have focal multiple microadenoma (nesidioblastosis) and was treated by radical pancreatoduodenectomy. Operative Management Before evaluation by us, 20 patients (22%) had at least one previous operation performed elsewhere (as many as four procedures) for peptic ulceration. A wide array of TABLE 4. Tumor Involvement in Patients With Zollinger-Ellison Syndrome

Primary Tumor Location Pancreas (n = 42) Head Body Tail Uncinate Multiple sites Duodenum (n = 13) Stomach (n = 3) Retroperitoneum (n = 1) Unknown primary (n = 31) Metastases (n = 34) Lymph nodes Hepatic Adrenalt Pulmonaryt

563

1.0

Intraoperative Localization

Sporadic

MEN-I

12

0 0 0 0 6* 1 1

11

6 1

6 12 2 0 25

1 6

75

15

10 19 2 2

4 1 0 0

33

5

* Two patients had synchronous duodenal tumors. t All four patients also had hepatic metastases.

> co

0.8

.0

0.6

C

0.4

.2 (D

0.2 _-

1.0-3.9 cm 24.0 cm

F P = 0.028

0

0

1

2

3

5

4

6

7

8

9

10

Years FIG. 1. Location of primary gastrinoma (n

=

90) in relation to the gas-

trinoma triangle.

operative procedures were performed on this heterogeneous group of patients at our institution over the 33 years surveyed (Table 5). Five procedures were done on an emergency basis (only one since 1976). A total of 12 patients underwent surgical re-exploration by us for recurrent symptoms of ZES after their initial procedure (Table 6). Two patients with metastatic disease subsequently required bilateral adrenalectomy for control of Cushing's syndrome related to ectopic adrenocorticotropic hormone production by the islet cell tumor. A single patient had enucleation of two pancreatic gastrinomas (removed elsewhere) 20 years after total gastrectomy had been performed by us. Although 40 patients had total gastrectomy performed at the Mayo Clinic, only three such procedures have been TABLE 5. Operative Management of Zollinger-Ellison Syndrome

Initial Mayo Procedure

No.

Total gastrectomy Total gastrectomy + distal pancreatectomy Total gastrectomy + enucleation Total gastrectomy + hepatic metastasis excision Distal pancreatectomy Distal pancreatectomy + enucleation, distal pancreatectomy + vagotomy, distal pancreatectomy + intraoperative radiotherapy, distal pancreatectomy + hepatic metastasis excision Enucleation Whipple procedure

22

Miscellaneous Tumor biopsy Partial gastrectomy Truncal vagotomy Partial gastrectomy + vagotomy Right hepatectomy, hepatic dearterialization, palliative gastrojejunostomy, palliative cholecystojejunostomy, left nephrectomy + tumor biopsy, aortofemoral bypass graft + duodenotomy Emergency procedures Total gastrectomy Vagotomy + pyloroplasty

Biopsy Partial gastrectomy + vagotomy Total

4 3 1 11

13 4 8 4 3 2

1 each

2 I I I

90

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Ann. Surg. * June 1992

TABLE 6. Follow-up Operative Procedurefor Patients With Symptoms ofZollinger-Ellision Syndrome

Time Initial Procedure

Age

Sex

MEN-I

54 54 52

M M F

No No No

Distal pancreatectomy Enucleation Whipple procedure

60 48 50 46 57 41 44 36 49

M F M F M F F F F M

No No No No No No No Yes Yes Yes

Partial gastrectomy Partial gastrectomy Partial gastrectomy Truncal vagotomy* Partial gastrectomy + truncal vagotomy Distal pancreatectomy Total gastrectomy Truncal vagotomy Distal pancreatectomy Enucleation

41 *

Emergency procedure.

Lapse

Secondary Procedure

5.0 mo 7.5 yr 1.3 yr

Enucleation Total gastrectomy Total gastrectomy + hepatic metastasis excision Tumor biopsy Total gastrectomy Total gastrectomy Total gastrectomy Partial gastrectomy

11.0 yr 2.6 yr 4.3 yr 14.0 days 1.0 mo 1.0 yr 20.0 yr 3.0 mo 6.0 mo 9.5 yr

Right hepatectomy Enucleationt Total gastrectomy Total gastrectomy Total gastrectomy

t Performed elsewhere.

performed on ZES patients since 1977, and just one since 1980. Five of 23 ZES patients with an intact gallbladder after total gastrectomy subsequently required cholecystectomy for symptomatic cholelithiasis. Hospitalization

Patients were hospitalized an average of 17 days (range, 2 to 70 days; median, 13). Twenty-four patients (27%) had 30 postoperative complications (Table 7). Three patients required reoperation related to postoperative complications (gastric bleeding, small bowel obstruction, and jejunojejunostomy leak). Overall 30-day operative mortality rate was 4%. Follow-up

Fifty-one patients remain alive at an average of 11 years after initial operation. Ten patients (11%) remain eugastrinemic off all medication, ranging from 1 to 17 years after surgical excision of the primary gastrinoma (duodenum, 6; stomach, 3; pancreatic head, 1). Of five patients

tested, four have normal postoperative secretin-stimulated levels. Twelve patients refrain from medication but have intermittent symptoms of gastric hypersecretion (epigastric pain or diarrhea). The remaining 29 patients are asymptomatic on medication. Cause of death in 39 patients was due to tumor progression (24), postoperative deaths (4), peptic ulcer disease (2), and non-ZES related deaths (9). Overall 5- and 10year survival for the study group was 76% and 68%, respectively. Five- and 10-year survival for an age- and sexmatched control population was 93% and 88%, respectively. Prognostic Factors for Survival

Patient outcome (long-term survival) correlated significantly with primary tumor size, primary tumor location, and degree of tumor involvement (Table 8). Significant prognostic factors were important at both 5- and 10-year intervals (Figs. 2, 3, 4). TABLE 8. Long-term Survival: Prognostic Factors

TABLE 7. Postoperative Complications in 24 Patients

Complication Symptomatic peptic ulcer disease Gastrointestinal bleeding Wound infection Ileus Pneumonia

Urinary tract infection Small bowel obstruction Esophagojejunostomy leak Myocardial infarction Jejunojejunostomy leak Intra-abdominal abscess

Sepsis Total * Postoperative deaths.

p

No. 4 4* 4 4 3* 3 2 2 1*

I I 1*

30

Variable Attempted surgical cure Baseline preoperative gastrin level Date of operation (before 1977 vs. after 1977) Emergency vs. elective procedure Sex MEN-I vs. sporadic Metastatic involvement Patient age Tumor location Tumor size Type of operative procedure *

p < 0.05.

p

(MEN-I,

(n = 90)

n = 15)

0.972 0.183

0.982

0.385 0.186 0.135 0.927 0.0004* 0.451 0.006* 0.028* 0.390

0.170

0.289 0.372 0.229 0.527 0.667 0.932

Vol. 215 * No. 6

SURGICAL TREATMENT OF THE ZOLLINGER-ELLISON SYNDROME

565

1.0

2!

0.8

.0 0

0.6

C

0.4

Multiple

I

Head

.2

Body

Cf) 0.2

Tail

Pancreas

0 0

1

2

3

4

5

6

7

8

10

9

Years FIG. 2. Correlation of primary tumor location (n survival.

=

90) with long-term

lGastrinoma triangle'

Multicentric

FIG. 4. Correlation of overall tumor involvement (n

Multiple Endocrine Neoplasia Type 1

=

90) with long-

term survival.

The 15 patients with ZES as a manifestation of MENI had a variety of pathologic lesions and subsequently underwent varied surgical management. Gastrinomas were identified in nine patients (multicentric in pancreas, 4; multicentric in pancreas and duodenum, 2; duodenum, 1; retroperitoneum, 1; and stomach, 1) (Table 4). Three such patients had metastatic involvement (lymph nodes, 2; liver, 1). Six patients had no primary gastrinoma identified, although a single patient did have metastatic nodal disease. Surgical management consisted of total gastrectomy (5), tumor enucleation (3), partial gastrectomy (2), distal pancreatectomy (2), truncal vagotomy (2), and tumor biopsy (1). Postoperative complications were minimal (wound infection, 2; pneumonia, 1; urinary tract infection, 1), with no postoperative deaths. Three patients required reoperation for persistent peptic ulcer disease (Table 6). Eight patients remain alive. Deaths were attributable to tumor progression (2), peptic ulcer disease (1), and nonZES-related deaths (4). No patient was rendered eugastrinemic despite six patients who underwent duodenotomy with excision of a duodenal gastrinoma in three. Significant prognostic factors (Table 8) were not identified for this subset of 15 patients with MEN-I. Long-

term survival of MEN-I patients was, however, equivalent to that of patients with sporadic disease.

Total Gastrectomy A total of 40 patients (24 men, 16 women; average age, 48 years) underwent total gastrectomy as either a primary or secondary procedure (Tables 5 and 6) to specifically control the symptoms ofZES. Ten patients (25%) incurred major complications (anastomotic leak, 3; intra-abdominal abscess, 2; prolonged ileus, 2; sepsis, 2; small bowel obstruction necessitating reoperation, 1; gastrointestinal bleeding, 1; and myocardial infarction, 1). Two patients died as a direct result of postoperative complications (5% operative mortality rate). Average duration of hospitalization was 20 days (range, 8 to 70 days). Twenty-one patients remain alive at an average of 16.5 years after total gastrectomy. Diarrhea remains problematic in four patients, whereas the remainder ofthis group has stopped all usage of pharmacologic therapy. Of the 19 deaths in this group, 12 deaths resulted from tumor progression, five from unrelated causes, and two from complications of the procedure.

Discussion

1.0 .

pancreatic gastrinomas

0.8

metastases

0.6

IE 0.4 nm.astase, 0.2

The epidemiologic data of patients with ZES have been fully elucidated.'2 With a slight male predominance existing, identification ofZES may occur in early childhood through octogenerians.'3 Roughly 75% of patients have sporadic disease, whereas the remaining one fourth of patients have hypergastrinemia as a manifestation of MENI. Our study group "conforms" to these epidemiologic norms.

Years

FIG. 3. Correlation of identified primary tumor size (n term survival.

=

59) with long-

Epigastric pain predominates in patients with ZES and is usually the impetus for patients to seek medical advice. Ellison and Wilson'4 found in a review of a collective

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FARLEY AND OTHERS

registry in 1964 that over one half of the patients had ulceration of the duodenal bulb, whereas 26% had ulceration of the esophagus or jejunum. Severe diarrhea was a prominent symptom in 36% of patients and the sole symptom in 7%. The symptom complex of the current study group is quite similar, with a long prelude before the diagnosis of ZES (as long as 18 years in one patient). Serum gastrin quantification (baseline and secretinstimulated) has proven extremely effective since the development of a gastrin radioimmunoassay in 1968.5 However, false-negative results as high as 10% have been recorded with secretin stimulation by some authors, 15-17 and baseline fasting serum gastrin levels have been reported to be nondiagnostic in more than 50% of ZES patients.'5 From our admittedly select group of patients, only two had normal preoperative serum baseline gastrin values (200 pg/mL within 20 minutes of secretin injection. When a thorough history and physical examination raises the suspicion of ZES, confirmation should be obtained by documenting the presence of hypergastrinemia and by demonstrating a rise in serum gastrin levels of >200 pg/mL after secretin stimulation (positive secretin test). If gastric analysis is done, the usual findings are an increased volume of gastric secretion (8 to 12 L/24 hours), increased basal acid secretion (> 15 mmol/hr), and a ratio of basal versus stimulated (pentagastrin) acid secretion of more than 60%. Currently, there are essentially four issues that continue to provide fuel for heated debate whenever ZES is discussed: 1. How may tumor localization be improved on both before and during operation? 2. Is the currently available, extremely effective medical therapy preventing potentially curable patients the benefit of surgical exploration? 3. What is the current role of total gastrectomy? 4. Is the nihilistic surgical attitude concerning patients with MEN-I justified? Tumor Localization

The ability to localize the primary tumor and detect any liver metastases before operation maximizes the surgeon's ability to care for the ZES patient. As physician awareness and suspicion of ZES increases and laboratory analysis improves, gastrinomas causing ZES are being detected at an earlier stage and thus are becoming more difficult to image. In concert with the present series, 30% to 50% of primary gastrinomas have not been detected before operation by radiographic analysis.'8 Controversy

Ann. Surg. * June 1992

persists regarding the optimal strategy of tumor localization. Preoperative computed tomography with intravenous and gastrointestinal contrast, coupled with intraoperative ultrasound in selected cases, is our method of choice (for localization). The usefulness of computed tomography scanning to detect hepatic metastases (21 cm) or primary gastrinomas (.1 cm) is proven.'9'20 The accurate resolution to delineate microgastrinomas (

The Zollinger-Ellison syndrome. A collective surgical experience.

A retrospective study of 90 surgically treated patients with the Zollinger-Ellison syndrome seen from 1958 through 1990 was performed. Fifteen patient...
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