Acta Med Scand 206: 223-227, 1979
Streptozotocin Treatment of a Pancreatic Tumour Producing VIP and Gastrin Associated with Verner-Morrison Syndrome K . Oberg, H. Bostrom, J. Fahrenkrug, J. F. Dymling 0. B. Shaffalitsky de Muckadell and G. Lundqvist From the Departments of Internal Medicine and Clinical Chemistry, University Hospital, Uppsala, the Department of Endocrinology, M a h o General Hospital, Malmo, Sweden, and the Department of Clinical Chemistry. Bispebjerg Hospital, Copenhagen, Denmark
ABSTRACT. A 57-year-old male patient with metastasizing non-beta islet cell carcinoma of the pancreas is described. Both gastrin and VIP levels were elevated and the patient suffered from a syndrome of pancreatic cholera and hyperacidity. The tumour contained gastrin and VIP as demonstrated by immunofluorescence.The patient also had a history of familial renal stone formation and parathyroid nodular hyperplasia. Resection of pancreatic tumour in 1973 resulted in four years without symptoms. In 1977 definite signs of multiple hepatic metastases appeared. These signs disappeared after streptozotocin given in a dosage of 2 g three times at weekly intervals. The patient has remained well for 20 months after this treatment. The causative agents for the clinical syndrome in this case are discussed in view of circulating hormone levels. Key wwrds: Verner-Morrison syndrome, VIP, gastrin, streptozotocin treatment. Acta Med Scand 206: 223, 1979.
The syndrome of watery diarrhoea, hypokalaemia and achlorhydria (WDHA syndrome, pancreatic cholera or Verner-Morrison syndrome) associated with non-beta islet cell tumour of the pancreas was first described by Verner and Morrison in 1958 (24). Although most of the cases are associated with pancreatic tumours, the syndrom can be produced by various tumour types (20). The causative agentb) is still not firmly established, although the frequent presence of increased plasma and tumour concentration of vasoactive intestinal polypeptide (VIP) (2,20), a 28-amino acid peptide (21) known to cause the symptoms seen in this syndrome, favour the role of VIP. In some patients, however, the
hormonal overproduction involves more than one humoral agent. A few cases have been reported in which the responsible agent is supposed to be pancreatic polypeptide (PP) (13) or prostaglandin E (9). Streptozotocin, an antitumour antibiotic, has recently been used successfully in the treatment of the WDHA syndrome (6, 11, 22). In this report we describe successful streptozotocin treatment of a patient with a pancreatic carcinoma producing both VIP and gastrin. CASE REPORT A male, born in 1920, was surgically explored in 1%9 because of renal stones and severe hypercalcaemia (S-Ca >3.0 mmol/l). Two macroscopically normal parathyroids were left intact and one macroscopically enlarged parathyroid was removed. Morphologically this demonstrated a nodular hyperplasia, consisting partly of oxyphilic cells, partly of chief cells. S-Ca returned to normal after operation. His father and two brothers, one of whom had been operated on for parathyroid hyperplasia, had had recurrent renal stones. In Nov. 1972, the patient complained of recurrent short episodes of watery diarrhoea since July. The S-Ca was normal at this time. In Dec. a gastric ulcer was diagnosed, which healed on conservative medical treatment. S-Ca was still normal. In June 1973 he became acutely ill and was readmitted to Malmo General Hospital with abdominal pains and large watery diarrhoeas 9-10 times daily. Laboratory tests revealed severe dehydration, hypercalcaemia and hypokalaemia. His general condition
Abbreviations: WDHA syndrome = the syndrome of watery diarrhoea, hypokalaemia and achlorhydria, VIP = vasoactive intestinal polypeptide, PP = pancreatic polypeptide, ZE syndrome = Zollinger-Ellison syndrome. Actu Med Scund 206
224
K . Oherg et al. Gastrin
pmol/
The patient was initially treated with i.v. infusion of electrolytes (potassium 80-120 mEq/d.), nutrients and fluids (4-6 l/d.). Thereafter a course of streptozotocin was given intravenously in three doses of 2 g each at intervals of one week. Already after two doses he passed one formed stool daily. Three months later he had gained 7 kg in weight and all laboratory test values had become normal (Table I), except for PP and S-calcium. At reexamination 20 months after streptozotocin treatment the patient was quite well and had resumed his ordinary work. Computer tomography of the abdomen and liver scintigraphy as well as laboratory tests were normal, except for S-Ca which remained slightly elevated and S-PTH which was elevated to 0.54 pgll. The patient fulfills the criteria of multiple endocrine adenomatosis type I with pancreatic tumours and hyperplasia of parathyroids.
401
201
10
L D O R A T O R Y METHODS
1 I
I
I
I TIME
Secrle9in 2o
30
mi
n
15 unit/kg bw I V
Fig. 1 . Serum gastrin after administration of secretin as a bolus injection.
deteriorated in spite of i.v. fluid supplements. The stool volume varied between 5 and 8 1 per day. In the Intensive Care Unit the patient required respiratory assistance and approximately 10 I of fluid intravenously, including 200400 mmol of potassium daily. The fasting secretion of hydrochloric acid was very high and a large duodenal ulcer was found. Anghiography of the coeliac artery yielded a large, partly calcified tumour in the pancreatic tail. On laparotomy in July 1973 a partial resection of the pancreas was performed. There were no macroscopical metastases in the liver or the other abdominal organs. Morphologically the resected part of the pancreas contained three separate non-beta islet cell carcinomas. Immunofluorescent studies demonstrated a positive reaction with antibodies to VIP and gastrin. Postoperatively the patient recovered completely clinically. The patient remained well but slightly hypercalcaemic until March 1977. At that time the diarrhoeas recurred rather abruptly. He was admitted in early April with four or five diarrhoeas daily and had at that time experienced a weight loss of 6 kg. He deteriorated rapidly after admission. Multiple liver metastases were visualized on scintigraphy and angiography. He was referred to the Medical Department, University Hospital, Uppsala, in May 1977. At that time stool volumes varied between 2 and 9 I daily. The basal gastric acid output was low (0 pmol/min) and after pentagastrin stimulation 136 Fmol/min (normal response). X-rays of the sella turcica and lungs as well as computer tomography of the skull were normal. Acfo Mrd Scund 206
Routine haematological and serum analyses were performed at the Laboratory of Clinical Chemistry, University Hospital, Uppsala. Gastrin, PP, VIP and somatostatin were determined by radioimmunoassay procedures ( I , 5 , 7, 16).
LABORATORY RESULTS The laboratory findings before and after medical treatment are summarized in Table I. Increased gastrin, PP and VIP levels were found prior to the treatment. Because of hypergastrinaemia, earlier episodes of ventricular and duodenal ulcers and gastric hyperacidity, a secretin test was performed. As shown in Fig. 1, secretin injection caused a marked
Table I . Laborutory tests before and three months after treatment with streptozotocin
ESR (mmlh) b-Hb (g/l) S-albumin (g/l) S-calcium (mmol/l) S-phosphate (mmol/l) S-potassium (mmol/l) S-natrium (mmol/l) fb-glucose (mmol/l) S-gastrin (pmol/l) S-PP (pg/ml) p-VIP (pmol/l) p-somatostatin (pgll) S-PTH (pg/l) S-calcitonin (pmol/l)
Before
After
47 96 30 2.74 0.8 2.7 140 5.0 114.7 866 210 78 0.32 480
10 143 42 2.83 1.1 4.0 140 4.5 32.1 1320 45.0
Normal values
2-15 134-166 42-55 2.20-2.60 0.76-1.44 3.2-5.1 134-146 3.3-5.7 4 5
Streptozotocin Treatment of a Pancreatic Tumour Producing VIP and Gastrin Associated with Verner-Morrison Syndrome K . Oberg, H. Bostrom, J. Fahrenkrug, J. F. Dymling 0. B. Shaffalitsky de Muckadell and G. Lundqvist From the Departments of Internal Medicine and Clinical Chemistry, University Hospital, Uppsala, the Department of Endocrinology, M a h o General Hospital, Malmo, Sweden, and the Department of Clinical Chemistry. Bispebjerg Hospital, Copenhagen, Denmark
ABSTRACT. A 57-year-old male patient with metastasizing non-beta islet cell carcinoma of the pancreas is described. Both gastrin and VIP levels were elevated and the patient suffered from a syndrome of pancreatic cholera and hyperacidity. The tumour contained gastrin and VIP as demonstrated by immunofluorescence.The patient also had a history of familial renal stone formation and parathyroid nodular hyperplasia. Resection of pancreatic tumour in 1973 resulted in four years without symptoms. In 1977 definite signs of multiple hepatic metastases appeared. These signs disappeared after streptozotocin given in a dosage of 2 g three times at weekly intervals. The patient has remained well for 20 months after this treatment. The causative agents for the clinical syndrome in this case are discussed in view of circulating hormone levels. Key wwrds: Verner-Morrison syndrome, VIP, gastrin, streptozotocin treatment. Acta Med Scand 206: 223, 1979.
The syndrome of watery diarrhoea, hypokalaemia and achlorhydria (WDHA syndrome, pancreatic cholera or Verner-Morrison syndrome) associated with non-beta islet cell tumour of the pancreas was first described by Verner and Morrison in 1958 (24). Although most of the cases are associated with pancreatic tumours, the syndrom can be produced by various tumour types (20). The causative agentb) is still not firmly established, although the frequent presence of increased plasma and tumour concentration of vasoactive intestinal polypeptide (VIP) (2,20), a 28-amino acid peptide (21) known to cause the symptoms seen in this syndrome, favour the role of VIP. In some patients, however, the
hormonal overproduction involves more than one humoral agent. A few cases have been reported in which the responsible agent is supposed to be pancreatic polypeptide (PP) (13) or prostaglandin E (9). Streptozotocin, an antitumour antibiotic, has recently been used successfully in the treatment of the WDHA syndrome (6, 11, 22). In this report we describe successful streptozotocin treatment of a patient with a pancreatic carcinoma producing both VIP and gastrin. CASE REPORT A male, born in 1920, was surgically explored in 1%9 because of renal stones and severe hypercalcaemia (S-Ca >3.0 mmol/l). Two macroscopically normal parathyroids were left intact and one macroscopically enlarged parathyroid was removed. Morphologically this demonstrated a nodular hyperplasia, consisting partly of oxyphilic cells, partly of chief cells. S-Ca returned to normal after operation. His father and two brothers, one of whom had been operated on for parathyroid hyperplasia, had had recurrent renal stones. In Nov. 1972, the patient complained of recurrent short episodes of watery diarrhoea since July. The S-Ca was normal at this time. In Dec. a gastric ulcer was diagnosed, which healed on conservative medical treatment. S-Ca was still normal. In June 1973 he became acutely ill and was readmitted to Malmo General Hospital with abdominal pains and large watery diarrhoeas 9-10 times daily. Laboratory tests revealed severe dehydration, hypercalcaemia and hypokalaemia. His general condition
Abbreviations: WDHA syndrome = the syndrome of watery diarrhoea, hypokalaemia and achlorhydria, VIP = vasoactive intestinal polypeptide, PP = pancreatic polypeptide, ZE syndrome = Zollinger-Ellison syndrome. Actu Med Scund 206
224
K . Oherg et al. Gastrin
pmol/
The patient was initially treated with i.v. infusion of electrolytes (potassium 80-120 mEq/d.), nutrients and fluids (4-6 l/d.). Thereafter a course of streptozotocin was given intravenously in three doses of 2 g each at intervals of one week. Already after two doses he passed one formed stool daily. Three months later he had gained 7 kg in weight and all laboratory test values had become normal (Table I), except for PP and S-calcium. At reexamination 20 months after streptozotocin treatment the patient was quite well and had resumed his ordinary work. Computer tomography of the abdomen and liver scintigraphy as well as laboratory tests were normal, except for S-Ca which remained slightly elevated and S-PTH which was elevated to 0.54 pgll. The patient fulfills the criteria of multiple endocrine adenomatosis type I with pancreatic tumours and hyperplasia of parathyroids.
401
201
10
L D O R A T O R Y METHODS
1 I
I
I
I TIME
Secrle9in 2o
30
mi
n
15 unit/kg bw I V
Fig. 1 . Serum gastrin after administration of secretin as a bolus injection.
deteriorated in spite of i.v. fluid supplements. The stool volume varied between 5 and 8 1 per day. In the Intensive Care Unit the patient required respiratory assistance and approximately 10 I of fluid intravenously, including 200400 mmol of potassium daily. The fasting secretion of hydrochloric acid was very high and a large duodenal ulcer was found. Anghiography of the coeliac artery yielded a large, partly calcified tumour in the pancreatic tail. On laparotomy in July 1973 a partial resection of the pancreas was performed. There were no macroscopical metastases in the liver or the other abdominal organs. Morphologically the resected part of the pancreas contained three separate non-beta islet cell carcinomas. Immunofluorescent studies demonstrated a positive reaction with antibodies to VIP and gastrin. Postoperatively the patient recovered completely clinically. The patient remained well but slightly hypercalcaemic until March 1977. At that time the diarrhoeas recurred rather abruptly. He was admitted in early April with four or five diarrhoeas daily and had at that time experienced a weight loss of 6 kg. He deteriorated rapidly after admission. Multiple liver metastases were visualized on scintigraphy and angiography. He was referred to the Medical Department, University Hospital, Uppsala, in May 1977. At that time stool volumes varied between 2 and 9 I daily. The basal gastric acid output was low (0 pmol/min) and after pentagastrin stimulation 136 Fmol/min (normal response). X-rays of the sella turcica and lungs as well as computer tomography of the skull were normal. Acfo Mrd Scund 206
Routine haematological and serum analyses were performed at the Laboratory of Clinical Chemistry, University Hospital, Uppsala. Gastrin, PP, VIP and somatostatin were determined by radioimmunoassay procedures ( I , 5 , 7, 16).
LABORATORY RESULTS The laboratory findings before and after medical treatment are summarized in Table I. Increased gastrin, PP and VIP levels were found prior to the treatment. Because of hypergastrinaemia, earlier episodes of ventricular and duodenal ulcers and gastric hyperacidity, a secretin test was performed. As shown in Fig. 1, secretin injection caused a marked
Table I . Laborutory tests before and three months after treatment with streptozotocin
ESR (mmlh) b-Hb (g/l) S-albumin (g/l) S-calcium (mmol/l) S-phosphate (mmol/l) S-potassium (mmol/l) S-natrium (mmol/l) fb-glucose (mmol/l) S-gastrin (pmol/l) S-PP (pg/ml) p-VIP (pmol/l) p-somatostatin (pgll) S-PTH (pg/l) S-calcitonin (pmol/l)
Before
After
47 96 30 2.74 0.8 2.7 140 5.0 114.7 866 210 78 0.32 480
10 143 42 2.83 1.1 4.0 140 4.5 32.1 1320 45.0
Normal values
2-15 134-166 42-55 2.20-2.60 0.76-1.44 3.2-5.1 134-146 3.3-5.7 4 5
