Archives of Disease in Childhood, 1980, 55, 226-238

Short reports

Zollinger-Ellison syndrome in a child: medical treatment with cimetidine

D P DRAKE, A G MACIVER, AND J D ATWELL

Wessex Centre for Paediatric Surgery, and Department ofPathology, Southampton General Hospital

SUMMARY A 12-year-old boy presented withintestinal obstruction associated with duodenal andoesophageal ulceration. At laparotomy he wasfound to have an islet cell tumour in the right lobe ofthe liver. Gastroenterostomy was performed. Raisedlevels of serum gastrin were detected. Treatmentwith cimetidine has produced satisfactory control ofhis symptoms for 16 months, and is an acceptablealternative to total gastrectomy in childhood.

The syndrome described by Zollinger and Ellison in19551 is rare in children. It is due to either single ormultiple tumours composed of gastrin-secreting cells.Most tumours arise in the pancreas; a few are foundadjacent to the pancreas.2 This report describes theclinical and pathological details of a boy with

Zollinger-Ellison syndrome in which a gastrinomawas detected in the liver. Successful management hasbeen achieved with cimetidine.

Case report

A 12-year-old boy weighing 35 kg presented inOctober 1977 with a 6-month history of intermittentepigastric pain, vomiting, and occasional haema-temeses. He had been passing several bulky stoolseach day for 12 months and had lost 7 kg in weight.There was no family history of endocrine disorder orpeptic ulceration; his parents and three older siblingswere alive and well. Physical examination showedepigastric tenderness but no other abnormality.Barium meal examination showed widening of theduodenal loop and dilatation of the proximal

4di

Fig. 1 Liver containing isletcell tumour. The tumour hasa gyriform pattern. Haematoxylinand eosin x 360.

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Zollinger-Ellison syndrome in a child: medical treatment with cimetidine 227

duodenum, while endoscopy showed inflammation ofthe lower oesophagus and focal duodenal ulcerationwith extensive acute inflammation.Duodenal obstruction necessitated laparotomy, at

which was found an oedematous mass affectingthe head of the pancreas and the second part of theduodenum. A white tumour, 4 cm diameter, in theright lobe of the liver was biopsied. Gastro-jejunostomy was performed.

Histological examination of biopsies of stomach,duodenum, and jejunum showed mucosal oedemaand acute inflammation of the superficial laminapropria throughout. Acute ulceration was present inthe oesophagus, while the gastric antrum showedpronounced hyperplasia of the parietal cells. Theliver biopsy contained a tumour, composed ofribbons of cells, which had the appearance of anislet cell tumour (Fig. 1). This was confirmed byEM examination which showed that most tumour

cells contained large numbers of cytoplasmicvesicles, 300-350 nm diameter, with greyish, finelygranular contents (Fig. 2). A few cells had densely-cored vesicles, 55 nm diameter, similar to thegranules found in the a-cells of the islets ofLangerhans.

Postoperatively, up to 6 litres of gastric fluid aday were produced and further gastrointestinalhaemorrhage necessitated a second laparotomy tounder-run an anastomotic ulcer.

Investigations showed faecal fat 86 mmol/24 h(24 -4 g/24 h) (normal < 18 mmol/24 h; 5 1 g/24 h),fasting serum gastrin 798 ng/l (normal <105 ng/l),and plasma pancreatic polypeptide 240 pmol/l(normal < 100 pmol/l). Levels of gastric acidwere high despite the previous gastrojejunostomy.The following were normal: serum calcium 2-18mmol/l (8-7 mg/100 ml), plasma glucagon 5 pmol/l,serum vasoactive intestinal polypeptide <5 pmol/l,

Fig. 2 Portions of liver tumour cells containing many cytoplasmic vesicles. There is some minor variation in thesize and in the electrondensity of their contents. x 11 200.

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228 Drake, MacIver, and Atwell

and glucose tolerance. Coeliac and superiormesenteric angiograms showed no abnormality.Ultrasound examination showed a single lesion in theright lobe of the liver.

Intravenous cimetidine (6 mg/kg) quickly relievedhis epigastric pain and he was therefore started onmaintenance treatment with cimetidine, 1 g a day individed doses. His condition continued to improve,with a return to a full diet and a weight gain of 23 kgover 12 months. He is now able to take part in allschool activities. Fasting serum gastrin, 12 monthsafter starting treatment, is still raised (420 ng/l and284 ng/l on consecutive days), but he is well andsymptom-free.

Discussion

Pancreatic tumours are rare in childhood butinsulinomas,3 carcinomas of acinar and mixedorigin,4 and gastrinomas can occur.5-6 The definitivediagnosis of gastrinoma usually requires demonstra-tion of high levels of gastrin in fasting serum, butdetection of granules in the cytoplasm of tumourcells by EM examination can also help. There mayhowever be some variation in granule size and thegranules in our patient, who had vesicles measuring300-350 nm diameter, correspond to type II granulesof Greider et al.2 Immunofluorescence and immuno-peroxidase techniques can beusedtoshow the presenceof hormone in the cytoplasm of tumour cells7 but,once again, methods have had varied success.2 Theassociation of gastrinomas with neoplasms in otherendocrine organs is now well established,8 but, in areview of 15 children with the Zollinger-Ellison syn-drome, none had a second endocrine tumour.5 How-ever, even single tumours can produce more than onepancreatic hormone9 as, for example, in our patientwho had raised levels of both gastrin and pancreaticpolypeptide. Gastrinomas can occur in the pancreas,stomach, or duodenum7 but in some cases either alymph node or a hepatic deposit was found withoutdefinite localisation of a primary pancreatic orperiduodenal tumour.6 While it is possible that sucha tumour might arise in the liver, embryologicalremnants of pancreatic and gastric tissue are rare inthis site and are not mentioned by Willis.10The prognosis for the Zollinger-Ellison syndrome

depends more on the effects of gastrin than on thedegree of differentiation of the tumour. Assessmentof malignancy by the cytology of tumour cells is anunreliable predictor of behaviour2 but 60% of thetumours that have produced the Zollinger-Ellisonsyndrome are malignant, with metastases par-ticularly in the liver and lymph nodes." Totalgastrectomy has been found to improve prognosis,probably by the reduction of acid and secretin

production both of which contribute to steatorrhoeaand cause ulceration of oesophagus, stomach, andduodenum.5 12 There have been some reports of thetreatment of adults suffering from Zollinger-Ellisonsyndrome with H2-receptor antagonists, such asmetiamide and cimetidine,13-'4 with a satisfactoryresponse in up to two-thirds of them. The immediaterelief of symptoms and the subsequent clinicalimprovement in our patient shows that cimetidine issimilarly acceptable in childhood as an alternative tototal gastrectomy in the management of the Zollinger-Ellison syndrome if the tumour cannot be surgicallyexcised. No side effects of treatment have beenobserved.

We thank Dr Peter Johnston for referring hispatient, and Dr Stephen Bloom for invaluable adviceand for assays of gastrin, pancreatic polypeptide,glucagon, and vasoactive intestinal polypeptide.

References

Zollinger R M, Ellison E H. Primary peptic ulcerations ofthe jejunum associated with islet cell tumors of thepancreas. Ann Surg 1955; 142: 709-28.

2 Greider Marie H, Rosai J, McGuigan J E. The humanpancreatic islet cells and their tumors. II. Ulcerogenic anddiarrheogenic tumors. Cancer 1974; 33: 1423-43.

3 Rickham P P. Islet cell tumors in childhood. J PediatrSurg 1975; 10: 83-6.

4 Frable W J, StillW J S, Kay S. Carcinoma of the pancreas,infantile type. A light and electron microscopic study.Cancer 1971; 27: 667-73.

5 Wilson S D, Schulte W J, Meade R C. Longevity studiesfollowing total gastrectomy in children with the Zollinger-Ellison syndrome. Arch Surg 1971; 103: 108-15.

6 Buchta R M, Kaplan J M. Zollinger-Ellison syndrome ina nine year old child: a case report and review of thisentity in childhood. Pediatrics 1971 ; 47: 594-8.

7 Creutzfeld W, Arnold R, Creutzfeld Cora, Track N S.Pathomorphologic, biochemical, and diagnostic aspects ofgastrinomas (Zollinger-Ellison syndrome). Hum Pathol1975; 6: 47-76.

8 Isenberg J I, Walsh J H, Grossman M I. Zollinger-Ellison syndrome. Gastroenterology 1973; 65: 140-65.

9 Polak J M, Bloom S R, Adrian T E, Heitz P H, BryantM G, PearseAG E. Pancreatic polypeptide in insulinomas,gastrinomas, vipomas, and glucagonomas. Lancet 1976;1: 328-30.

10Willis R A. The borderland of embryology and pathology.2nd ed. London: Butterworth, 1962.Schein P S, DeLellis R A, KahnC R, Gorden P, Kraft A R.Islet cell tumours; current concepts and management.Ann Intern Med 1973; 79: 239-57.

12 Walsh J H, Grossman M I. Gastrin (second of two parts)NEnglJ Med 1975; 292: 1377-84.

13 Deveney C W, Deveney Karen S, Way L W. Zollinger-Ellison syndrome-23 years later. Ann Surg 1978; 188:384-93.

14 McCarthy D M. Report of the United States experiencewith cimetidine in Zollinger-Ellison syndrome and otherhypersecretory states. Gastroenterology 1978; 74: 453-8.

Correspondence to D P Drake FRCS, Department ofSurgery, Guy's Hospital, St Thomas Street, London SE19RT.

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