Endoscopic cure of the Zollinger-Ellison syndrome

Endoscopic cure of the Zollinger-Ellison syndrome Eugene Straus, Jean-Pierre Raufman, Shelby Samuel, Jerome D. Waye, David C. Metz, Joseph R. Pisegna, Robert T. Jensen,

MD MD MD MD MD MD MD

Advances in the pharmacological management of gastric acid hypersecretion in patients with ZollingerEllison syndrome have made it possible to control acid output and prevent peptic ulceration in virtually all patients. As a result, since tumor growth is becoming an important factor in determining long-term survival in many patients, attention is now being directed at the management of the gastrinoma itself. 1 Recent studies have shown that primary gastrinomas in the duodenal submucosa are more common than initially believed and may even be more common than primary gastrinomas of the pancreas. 1- 3 Endoscopic detection of duodenal gastrinomas has been reported rarely.4-8 However, with the increased awareness of the frequency of duodenal gastrinomas in Zollinger-Ellison syndrome, particularly with the use of endoscopic ultrasound, in the future, these may be more commonly localized endoscopically. This raises the possibility that primary duodenal gastrinomas may be diagnosed and resected endoscopically in some cases. 5 In this report, we describe the endoscopic removal of a duodenal gastrinoma from the afferent limb of a Billroth II anastamosis in a 74-year-old man. Following endoscopic therapy his fasting serum gastrin concentration and secretin provocative test became normal, suggesting cure of his Zollinger-Ellison syndrome.

with a pH of 2.0. A hand-aspirated 15-min collection returned 40 ml of gastric secretion with a pH of 1.7. Titration with 0.1 N NaOH resulted in an estimated BAO > 5 mEq/ hour. Fasting plasma gastrin was 450 pg/ml (normal = 41.7 ± 4.6 pg/ml (mean ± SE)). Intravenous injection of GIH pure natural secretin resulted in plasma gastrin concentrations of 625, 700, 650, 575, 450, and 400 pg/ml at 1, 5, 10, 15, 30, and 45 min, respectively. A diagnosis of ZollingerEllison syndrome (ZES) was made. Abdominal CT scan revealed no evidence of tumor. Exploratory surgery was declined by the patient. During the 8 years following the diagnosis of ZES, the patient was asymptomatic on treatment with H2 receptor antagonists and finally omeprazole (60 mg daily). Routine yearly imaging studies did not reveal the primary tumor and were negative for metastatic disease. In December 1990, during a routine upper endoscopic examination a 1.0-cm polypoid mass in the proximal portion of the afferent limb of his Billroth II anastomosis was identified. Histopathological examination of a forceps biopsy specimen indicated that the tumor was of neuroendocrine origin. Fasting plasma gastrin on February 7, 1991 was 300 pg/ml. On February 13, 1991 a 1.0-cm polypoid mass with a reddened, irregular surface was found adjacent to the ampulla of Vater (Fig. lA). The polyp was removed endoscopically using a wire snare and electrocautery (Fig. IB). Multiple biopsies were taken from the edge of the polypectomy site to ascertain whether any residual tumor was present. Histological examination of the polyp revealed a submucosal neuroendocrine tumor with positive immunohistochemical staining for gastrin. Six hours after the polypectomy the patient complained of abdominal pain. The following morning the patient had a temperature of 101.5°F, and x-rays of the abdomen revealed free air under the diaphragm. Abdominal pain increased over the next 24 hours and the patient was taken to the operating room where a 1.5-cm full-thickness perforation in the second portion of the duodenum was oversewn. The post-operative course was uneventful. A secretin test done on May 10, 1991 revealed normal fasting plasma gastrin of 50 pg/ml with no change in concentration following injection of secretin. The patient was taken off all medications and has been well during a 6-month follow-up period.

CASE REPORT

A 74-year-old man was first seen by one of us (E. S.) in May 1983 when he complained of several years of epigastric burning pain. There were no other symptoms. Twenty-five years earlier he had undergone a partial gastrectomy with vagotomy and Billroth II reconstruction for duodenal ulceration. He had then been asymptomatic for nearly 22 years. The patient's symptoms improved quickly after institution of treatment with cimetidine 300 mg four times daily. Endoscopic examination revealed six small intestinal ulcerations at the gastroenterostomy site. After a 12-hour fast, nasogastric intubation returned 70 ml of clear colorless fluid From the Division of Digestive Diseases, State University of New York-Health Science Center at Brooklyn, Brooklyn, New York, Division of Gastroenterology, City University of New York-Mount Sinai School of Medicine, New York, New York, and Digestive Diseases Branch, National Institutes of Health, Bethesda, Maryland. Reprint requests: Eugene Straus, MD, SUNY/HSCB, Box 1196,450 Clarkson Avenue, Brooklyn, New York 11203-2098. VOLUME 38, NO.6, 1992

DISCUSSION This patient's initial operation for acid-peptic disease was performed just 2 years after the description of ZES. 9 This was before gastrin was known to be the cause of the syndrome, and more than a decade before the first measurements of circulating gastrin were made by radioimmunoassay. The success of that initial surgery in keeping the patient free of symptoms and signs of acid-peptic disease for nearly 22 years suggest that the gastrinoma was not present at that time. The patient had symptoms of burning epigastric pain for nearly 3 years prior to the diagnosis of ZES. A recommendation for exploratory surgery was made but declined. The stable course with excellent control of symptoms, and the finding of a small tumor a 709

Figure 1. Videoendoscopic photographs of duodenal gastrinoma before (A) and after (B) snare polypectomy. A indicates ampulla of Vater; G indicates gastrinoma; and PS indicates polypectomy site.

decade after the presentation of symptoms and 8 years after the diagnosis, is typical of uncomplicated ZES. 10 ZES caused by single or multiple gastrinomas of the duodenal wall has been well described. 2-s, 10 Recent reports have observed a higher frequency of duodenal gastrinomas than had been generally appreciated,2 and suggest the possibility that virtually all cases of ZES in patients with multiple endocrine neoplasia type 1 result from duodenal gastrinomas. 11 A recent surgical series, that excluded patients with multiple endocrine neoplasia type 1, suggests that the majority of duodenal gastrinomas are proximally located; 71 % in the first portion, 21 % in the second portion, and only 8% in the more distal duodenum. 3 Nevertheless, rarely have these tumors been localized endoscopically2-S and only one well-documented cure of ZES resulting from endoscopic removal of a duodenal gastrinoma has been reported previously.5 Duodenal gastrinomas tend to be small and are generally not detected by computed tomography of the abdomen. 2-s,10 Frucht et a1. 2 have recommended routine endoscopic transillumination of the duodenum in all patients with ZES who undergo exploratory laparotomy for gastrinoma localization and resection. 710

Their study excluded patients with multiple endocrine neoplasia type 1 because of their belief that these patients generally have multiple microscopic pancreatic tumors which are not surgically curable. None of the 12 duodenal gastrinomas they found at surgery was detected during prior duodenoscopy. Although few submucosal duodenal gastrinomas have been described endoscopically, our patient's tumor was typical of the sessile mound with central depression previously called "volcano" or "donutlike.,,2-s These tumors may appear in any portion of the duodenum. 2-s,12-14 The demonstration that in some cases duodenal gastrinomas can be localized endoscopically suggests that careful endoscopic examination of the entire duodenum should be considered in patients with ZES. The current case raises the question as to whether endoscopic localization of a duodenal gastrinoma should provoke attempts at endoscopic extirpation of the tumor. Although they tend to be small tumors, their submucosal location and the requirement for complete removal, along with our experience in this case, suggest that an operative approach has advantages for the patient and is generally indicated. In addition to safer and more complete removal of the identified tumor(s), intra-operative endoscopic transillumination of the duodenum may demonstrate additional tumors and accurate staging can be accomplished. Finally, a recent large prospective study showed that recurrence following the removal of a duodenal gastrinoma approaches 50% at 5 years and is higher than occurs following the removal of a pancreatic gastrinoma. 15 The apparently higher malignant potential of duodenal gastrinomas underscores the advantages of a surgical approach.

REFERENCES 1. Jensen RT, Gardner JD. Zollinger-Ellison syndrome: clinical presentation, pathology, diagnosis, and treatment. In: Zakim D, Dannenberg AJ, eds. Peptic ulcer disease and other acid-related disorders. New York: Academic Research Associates, 1991:117211. 2. Frucht H, Norton JA, London JF, et al. Detection of duodenal gastrinomas by operative endoscopic transillumination. Gastroenterology 1990;90:1622-7. 3. Thorn AK, Norton JA, Axiotis CA, Jensen RT. Location, incidence and malignant potential of duodenal gastrinomas. Surgery 1991;110:1086-93. 4. Wu WC, Kengis J, Whalen G, Schulte WJ, Unger GF, Classen M. Endoscopic localization of a duodenal wall tumor in Zollinger-Ellison syndrome. Gastroenterology 1974;66:1237-9. 5. Gilhool WJ. Endoscopic diagnosis and removal of a duodenal wall gastrinoma. Am J Gastroenterol 1984;79:679-83. 6. Wadas DD, Foutch PG, Manne RK, Sanowski RA. Endoscopic diagnosis of a duodenal gastrinoma. Gastrointest Endosc 1988;34:430-1. 7. Piccione PR, Hamilton R, Kotler DP, Scholes J, McCray RS. The endoscopic localization of a gastrinoma in the afferent loop of a gastrojejunostomy. Gastrointest Endosc 1988;34:439-40. 8. Donovan DC, Dureza R, Jain U. Gastrinoma of the duodenum. Diagnosis by endoscopy. NYSJM 1979;79:1766-8. 9. Zollinger RM, Ellison EH. Primary peptic ulcerations of the

GASTROINTESTINAL ENDOSCOPY

jejunum associated with islet cell tumors of the pancreas. Ann Surg 1955;142:709-28. 10. Straus E. Ulcerogenic endocrine tumors. In: Berk JE, ed. Bockus gastroenterology. Vol 7, 4th ed. Philadelphia: WB Saunders, 1984:4467-79. 11. Pipeleers-Marichal M, Somers G, Willems G, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. N Engl J Med 1990;322:723-7. 12. Hoffmann JW, Fox PS, Wilson SD. Duodenal wall tumors and

the Zollinger-Ellison syndrome. Arch Surg 1973;107:334-9. 13. Antonioli DA, Dayal Y, Dvorak AM, Banks P. Zollinger-Ellison syndrome. Cure by surgical resection of a jejunal gastrinoma containing growth hormone releasing factor. Gastroenterology 1987;92:814-23. 14. Oberhelman HA. Excisional therapy for ulcerogenic tumors of the duodenum. Arch Surg 1972;104:447-53. 15. Norton JA, Doppman JL, Jensen RT. Curative resection in Zollinger-Ellison syndrome: results of a 10-year prospective study. Ann Surg 1992;215:8-1R.

Endoscopic diagnosis of gastric neuroendocrine carcinoma complicated by upper gastrointestinal hemorrhage

diabetes mellitus. She had a 50-pack/year smoking history and previously used alcohol. On admission her vital signs were notable for a blood pressure of 140/80 mm Hg, pulse 82 without orthostatic changes and with normal respirations and oral temperature. She was a mildly obese female in no apparent distress. The cardiopulmonary examination revealed scattered wheezes but no other abnormalities. The abdominal examination was notable for mild epigastric tenderness on deep palpation but without hepatosplenomegaly, masses, or rebound tenderness. Rectal examination revealed black guaiac-positive stool. There were no skin rashes or neurologic abnormalities identified. Admission laboratory data were notable for: hemoglobin, 8.5 g; hematocrit, 26.3; white blood cell count, 6800/mm 3 ; mean corpuscular volume, 73. The serum electrolytes, liver enzymes, and amylase were normal. Admission chest x-ray was without masses or active pulmonary disease and the electrocardiogram was within normal limits. Esophagogastroduodenoscopy the day of admission demonstrated a 2- X 2-cm "doughnut"-shaped lesion with a central ulceration in the body of the stomach along the greater curvature (Fig. 1). The remainder of the stomach and the esophagus were normal. The duodenal bulb was remarkable for multiple vascular ectasias; the second duodenum was normal. Multiple biopsies of the gastric lesion were taken, placed immediately in buffered 10% formalin, and submitted for pathologic evaluation. This revealed a neoplasm consisting of atypical small cells which infiltrated the gastric mucosa in ribbons and strands, characteristic of a neuroendocrine tumor. As the extent of cytologic atypia was greater than expected for a carcinoid tumor, the neoplasm was consistent with a well-differentiated neuroendocrine carcinoma. The patient experienced no further gastrointestinal bleeding during the hospitalization. Pre-operative abdominal and thoracic CT scanning were notable for a large subcarinal mass. CT-guided biopsy of the subcarinal lesion demonstrated tissue identical to the gastric lesion. Although metastatic disease was now documented, given the persistent epigastric pain and associated bleeding, surgical exploration with gastric wedge resection was then performed palliatively. Histopathologic examination of the gastric specimen revealed an infiltrating neuroendocrine neoplasm having similar cytologic features with the previous biopsy (Fig. 2). However, tumor cells appeared to extend from the superficial mucosa through the muscularis mucosae into the submucosa and was consistent with a primary mucosal site of origin. There was no evidence of adenocarcinomatous differentiation. Multiple tumor emboli were present within vessels;

Eric Steinberg, MD C. Mel Wilcox, MD David A. Schwartz, MD

The term neuroendocrine tumor is used to describe a broad spectrum of hormone-secreting neoplasms, each with a variable natural history. Primary lesions have been documented throughout the body, most commonly from the bronchial tree and lumenal gastrointestinal tract. 1- 3 A report of a partially obstructing colonic neuroendocrine carcinoma documented the annular appearance of the tumor. 4 Endoscopic reports of upper gastrointestinal tract lesions, however, have not previously been reported to our knowledge. The present case documents the endoscopic findings of a gastric neuroendocrine tumor complicated by upper gastrointestinal tract hemorrhage. CASE REPORT

A 58-year-old female presented with a 3-day history of melena and worsening epigastric pain. She described an approximately I-year history of intermittent mild to moderate epigastric pain associated with dark stools. Previous evaluation for these complaints 6 months prior to admission was notable for an upper gastrointestinal barium series revealing only gastroesophageal reflux. At that time, a barium enema examination revealed only sigmoid diverticulosis. Complete blood count, liver chemistry tests, as well as serum amylase were normal. She stated that over the 1 month prior to admission, the abdominal pain became persistent. An over-the-counter aspirin preparation was taken several days prior to admission for the pain. In addition, she noted an approximate 8-lb weight loss over the last 6 months. She denied hematemesis, history of gastrointestinal disease, or cardiopulmonary symptoms. Her past medical history was only remarkable for mild hypertension and diet-controlled From the Departments of Internal Medicine (Division of Digestive Diseases) and Pathology, Emory University School of Medicine and the Medical and Pathology Services, Grady Memorial Hospital, Atlanta, Georgia. Reprint requests: C. Mel Wilcox, MD, Division of Digestive Diseases, Emory University School of Medicine, 69 Butler Street, S.E., Atlanta, Georgia 30303. VOLUME 38, NO.6, 1992

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