Vipoma

Lesson of the Week

Failure to recognise secretory diarrhoea leads to inappropriate gastrointestinal investigations, delayed diagnosis of a vipoma, and avoidable morbidity

A wide range of gastrointestinal disorders may cause chronic diarrhoea in childhood. In a small proportion of cases the diarrhoea is due to active intestinal fluid secretion--secretory diarrhoea. It is essential to identify such cases because of important diagnostic implications. Patients with unexplained persistent watery diarrhoea should undergo a period of fasting; continuing diarrhoea indicates a secretory process. Secretory diarrhoea is confirmed by a raised stool sodium concentration. In the developed world the most likely explanation for persistent secretory diarrhoea may be an occult vipoma--a tumour that secretes vasoactive intestinal polypeptide.[1, 2] This is an uncommon tumour. The first two cases described here presented 25 and 15 years ago respectively, and the remaining four presented in the past 10 years. As these reports illustrate, however, vipomas are amenable to curative surgery. If the diagnosis is not considered, extensive gastrointestinal investigations may be undertaken, the diagnosis will be delayed, and avoidable morbidity will occur.

Case reports

Case 1

An 18 month old boy presented with an eight month history of diarrhoea, malnutrition, and abdominal distension. During eight weeks of inpatient investigation only a xylose absorption test proved abnormal. Coeliac disease was suspected, and he received a gluten free diet without intestinal biopsy. He was lost to follow up until 28 months of age, when he presented with a respiratory infection. A chest radiograph showed a tumour in the pulmonary right upper zone. The diarrhoea had persisted and he was severely malnourished.

Case 2

A 1 year old boy was referred with a two month history of watery diarrhoea, malnutrition, and abdominal distension. Investigations were normal, but a gluten free diet was started without intestinal biopsy. There was no improvement. Treatment with metronidazole for unproved giardiasis was ineffective. A "hypoallergenic" diet was prescribed, but the symptoms continued. After four months in hospital a barium contrast study with small bowel follow through unexpectedly showed the tumour as a space occupying lesion in the rectum. This was palpable on digital rectal examination. He was referred to the department of paediatric surgery, and by then he was severely malnourished and hypokalaemic (potassium concentration 2.8 mmol/l).

Case 3

A 2 year old boy was referred with a four month history of watery diarrhoea and weight loss. He had already been on a diet free of cows' milk for six weeks. A mass was palpable in the left lower abdomen. Serum electrolytes were normal. He was referred to the department of oncology, and ultrasonography showed a calcified left paravertebral tumour.

Case 4

An 8 month old boy was referred with a six week history of watery diarrhoea and weight loss. He had been starved and given oral rehydration solution repeatedly. During four weeks of inpatient investigations a xylose absorption test was abnormal and jejunal biopsy showed mild villous atrophy. He began a gluten free diet, but the diarrhoea continued. He was referred to the department of gastroenterology, and by then was severely malnourished, and hypokalaemic (potassium 1.9 mmol/l). Parenteral nutrition was begun and enteral feeds were stopped, but the diarrhoea persisted. Abdominal ultrasonography showed a calcified tumour in the right suprarenal area.

Case 5

A 16 month old boy was referred with a six month history of diarrhoea and poor weight gain. Trials of cows' milk exclusion and loperamide had been unsuccessful. During exacerbations he had been starved and given oral rehydration solution repeatedly. Toddler diarrhoea was suspected. At review three months later, his parents reported persistent watery diarrhoea, and he was admitted for investigation. He was hypernatraemic (sodium 151 mmol/l) and hypokalaemic (potassium 2.6 mmol/l), with a metabolic acidosis (bicarbonate 14 mmol/l). A further trial of cows' milk exclusion was started, but the diarrhoea persisted. At age 26 months he was referred to the department of gastroenterology, and by then was severely malnourished, hypokalaemic, and acidotic. The stool sodium concentration was markedly raised (81 mmol/l). Abdominal ultrasonography showed a calcified left suprarenal tumour.

Case 6

A 1 year old girl was referred with a three week history of watery diarrhoea. Before referral kaolin suspension had been prescribed, and she was starved and given oral rehydration solution repeatedly. She was hypokalaemic (potassium 2.9 mmol/l). The diarrhoea persisted during a 48 hour fast, and the stool sodium concentration was grossly raised (120 mmol/l). Nevertheless, the post-gastroenteritis syndrome was suspected, and she was started on a lactose free, protein hydrolysate formula. The diarrhoea continued, and after three weeks she was transferred to the department of gastroenterology, by which time she was seriously malnourished. Insertion of a urinary catheter allowed confirmation of severe diarrhoea during a 48 hour period of fasting (80 g/kg/day). She was hypokalaemic (potassium 2.3 mmol/l) with a metabolic acidosis (bicarbonate 16 mmol/l). Abdominal ultrasonography showed a left suprarenal tumour (fig 1).

[Figure 1 ILLUSTRATION OMITTED]

Excisions of tumours and follow up

In all six cases surgical exploration showed an encapsulated turnout, and in each case this was easily excised (fig 2). Histological examination established a diagnosis of ganglioneuroma in four and ganglioneuroblastoma in two (table). In every case, the diarrhoea immediately ceased after removal of the tumour. All the children were discharged from the hospital within two weeks. In case 4 a scrotal swelling was noted at routine follow up five years later, although diarrhoea had not recurred, and a well differentiated testicular ganglioneuroma was excised. Subsequently, he remained well over a five year follow up period. In the remaining five cases the disease did not recur over follow up periods of 5 to 14 years. The plasma vasoactive intestinal polypeptide concentration had been raised in each of the four children in whom this was measured, and after surgery it remained low on regular measurements.

[Figure 2 ILLUSTRATION OMITTED]

Discussion

In 1958 Verner and Morrison described a syndrome of severe watery diarrhoea and hypokalaemia in adults with non-[Beta] islet cell adenomas.[1] In children most vipomas are either ganglioneuromas or ganglioneuroblastomas, arising from the neural crest tissue of the sympathetic ganglia or the adrenal medulla.[2-6] Ganglioneuromas are well differentiated and benign, whereas ganglioneuroblastomas exhibit varying differentiation and the prognosis is less certain. Originally it was believed the watery diarrhoea was caused by catecholamine hypersecretion, a well recognised phenomenon with neural crest tumours.[7 8] In five of the children reported here the 24 hour urinary excretion of catecholamine metabolites was measured and was raised. In the 1970s it emerged that these turnouts also secreted vasoactive intestinal polypeptide.[9] Vasoactive intestinal polypeptide is a potent stimulant of adenylate cyclase, and this causes hypersecretion of water and electrolytes by the intestinal mucosa.[10] The plasma vasoactive intestinal polypeptide concentration was raised in all four of the children reported here in whom it was measured. Although hypokalaemia is not found in all cases, it is a common feature and was documented in four of these children.

Five of the six children were presumed to have a gastrointestinal disorder, and consequently the diagnosis was delayed. They spent from 3 to 18 (median 4) weeks in hospital undergoing investigations, and the eventual interval from referral to diagnosis ranged from 1 to [10.sup.4] months. All received empirical trials of treatment for various unproved gastrointestinal disorders. Three were repeatedly starved and given oral rehydration solution. Antidiarrhoeal agents were prescribed in two cases. One child received metronidazole for unconfirmed giardiasis. Two received diets free of cows' milk and one a "hypoallergenic" diet. In three cases coeliac disease was suspected and gluten free diets were prescribed. The duration of diarrhoea ranged from six weeks to 28 months (median 5 months). At the time of diagnosis the five children in whom a gastrointestinal disorder had been suspected were malnourished, with weight/height z scores (standard deviation scores) ranging from -2.0 to -3.3 (median -2.2) standard deviations below the mean. In case 3, because an abdominal mass was palpable at the time of referral, the diagnosis was established without delay, and he did not become malnourished. In each child once the diagnosis was established the tumour was successfully excised and the diarrhoea stopped immediately. The long term outcomes were excellent. Initial recognition of the secretory nature of the diarrhoea could have facilitated early diagnosis and unnecessary investigations and morbidity could have been avoided.

Secretory diarrhoea is a common disorder in developing countries, where pathogens that produce enterotoxin--such as enterotoxigenic Escherichia coli--are endemic.[11 12] Nowadays, however, persistent secretory diarrhoea is uncommon in the developed world.[12] Although bacterial and viral gastroenteritis may cause secretion, persistent secretory diarrhoea is rare. Certain rare inherited electrolyte transport defects, such as congenital chloride diarrhoea and congenital sodium diarrhoea, may be responsible, but these present in early infancy.[13] In older children secretory diarrhoea may occasionally occur in association with various major gastrointestinal disorders--for example, Crohn's disease and the short bowel syndrome--but in such cases the gut disorder is usually obvious. One important consideration is that secretory diarrhoea may be caused by surreptitious laxative administration in Munchausen syndrome by proxy.[14]

Secretory diarrhoea is characterised by watery stools, and, in contrast to osmotic diarrhoea, it persists while fasting. Biochemical analysis shows a raised stool sodium concentration (typically [is greater than] 50 mmol/l). The ionic contribution to stool osmolality can be calculated by using the formula 2 x (sodium concentration + potassium concentration), and in secretory diarrhoea this should be close to the measured osmolality on a fresh stool specimen. The severity of diarrhoea is easily underestimated because stool water is usually indistinguishable from urine. It is often helpful to insert a urinary catheter, so that the diarrhoea can be accurately quantified by recording the stool weight.

In summary, vipomas often present with diarrhoea as the only manifestation, and in such cases inappropriate gastrointestinal investigations and treatments might be undertaken. When investigating children with persistent watery stools it is essential to identify those with secretory diarrhoea: secretory diarrhoea continues when oral feeding is withheld; the diagnosis is confirmed by a raised stool sodium concentration. In such cases a vipoma should be suspected. Plasma vasoactive intestinal polypeptide concentration will be raised in these cases. The tumour is often visible with basic radiological techniques such as chest radiography and abdominal ultrasonography.

Clinical observations and findings at final diagnosis in six cases of childhood secretory diarrhoea

Clinical observations and findings at final diagnosis in six cases of childhood secretory diarrhoea

(*) Immunohistochemistry positive for a vipoma.

Contributors: MSM initiated the report and wrote the final version. AS compiled the cases with assistance from Mrs Sheila Parkes of the West Midlands Regional Children's Tumour Research Group and wrote the first draft. JRM provided advice on the manuscript and took part in discussions of the oncologicai aspects of the cases. MSM will act as guarantor for the paper.

Funding: None.

Competing interests: None declared.

[1] Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory diarrhoea and hypokalemia. Am J Med 1958;25:374-80.

[2] Bloom SR, Long RJ, Bryant MG, Mitchell SJ, Polak JM. Clinical, biochemical and pathological studies on 62 vipomas. Gastroenterology 1980;78:1143.

[3] Iida Y, Nose O, Kai H, Okada A, Mori T, Lee PK, et al. Watery diarrhoea with a vaso-active intestinal peptide-producing ganglioneuroblastoma. Arch Dis Child 1980;55:929-36.

[4] Long RG. Vasoactive intestinal polypeptide-secreting tumours (vipomas) in childhood. J Pediatr Gastroenterol Nutr 1983;2:122-6.

[5] Kaplan SJ, Holbrook CT, McDaniel HG, Buntain WL, Crist WM. Vasoactive intestinal peptide secreting tumors of childhood. Am J Dis Child 1980; 134:21-4.

[6] Long RG, Bryant MG, Mitchell SJ, Adrian TE, Polak JM, Bloom SR. Clinicopathological study of pancreatic and ganglioneuroblastoma tumours secreting vasoactive intestinal polypeptide (vipomas). BMJ 1981;282: 1767-70.

[7] Voorhess ML, Gardner LI. Studies of catecholamine excretion by children with neural tumours. J Clin Endocrinol Metab 1962;22:26-33.

[8] Scully RE, McNeily BU. Weekly clinicopathological exercises. N Engl J Med 1974;291:1351-5.

[9] Bloom SR, Polak JM, Pearse AGE. Vasoactive intestinal polypeptide and watery-diarrhoea syndrome. Lancet 1973;ii: 14-6.

[10] Schwartz CJ, Kimberg DV, Sheerin HE. Vasoactive intestinal peptide stimulation of adenylate cyclase and active electrolyte secretion in intestinal mucosa. J Clin Invest 1974;54:536-44.

[11] Acheson DWK. Enterotoxins in acute infective diarrhoea. J Infection 1992;24:225-45.

[12] Levine MM. Escherichia coli that caused diarrhea: enterotoxigenic, enteropathogenic, enteroinvasive, enterohemorrhagic and enteroadherent. J InJect Dis 1987;155:377-89.

[13] Desjeux J-F. Congenital transport defects. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, eds. Pediatric gastrointestinal disease. 2nd edition. St Louis: Mosby, 1996:792-815.

[14] Binder HJ. Pharmacology of laxatives. Ann Rev Pharmacol 1977;17: 355-65.

(Accepted 1 November 1999)

Department of Gastroenterology and Nutrition, Birmingham Children's Hospital, Birmingham B4 6NH

M S Murphy consultant paediatric gastroenterologist

A Sibal clinical fellow

Department of Oncology, Birmingham Children's Hospital

J R Mann consultant paediatric oncologist

Correspondence to: M S Murphy, Institute of Child Health, Clinical Research Block, Whittall Street, Birmingham B4 6NH m.s.murphy@ bham.ac.uk

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