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Resection of a vipoma of the pancreas in a 15-year-old girl
R e s e c t i o n of a V i p o m a of the P a n c r e a s in a 1 5 - Y e a r - O l d Girl By Richard W. Brenner, Lewis I. Sank, Michael B. Kerner, Gloria O. Schrager, Alberto Elguezabal, t and Joel Roth Summit, New Jersey 9 A 15-year-old girl had massive w a t e r y and proteinlosing diarrhea. She was found to have a pancreatic islet cell tumor secreting high levels of vasoactive intestinal polypeptide. Eighty-five percent pancreatic resection was needed to remove the tumor. She has normal serum VIP levels and no tumor recurrence 6 years later. 9 1986 by Grune & Stratton, Inc. INDEX W O R D S : Pancreatic islet cell tumor; vasoactive intestinal polypeptide; w a t e r y diarrhea syndrome; vipoma.
N T H E PAST three decades, reports have appeared of the association of non-beta islet cell adenoma or carcinoma of the pancreas? 4 tumors of the adrenal glands, 5 neural crest 6 and bronchus? and hyperplasia of the pancreatic islets in patients who have a syndrome combining severe water- and protein-losing diarrhea and hypokalemia with or without gastric achlorhydria. This constellation has also been named pancreatic cholera and most recently vipoma and the watery diarrhea syndrome.
I
CASE REPORT A.N., a 15-year-old white female, was admitted with two days of diarrhea up to ten times a day and vomiting. Similar massive secretory diarrhea had occurred over a 6-week period l t/2 years before. Diagnostic studies then did not detect either bowel disease or endocrine abnormality. There was a large normal gallbladder (by ultrasound), which compressed the hepatic flexure during barium enema examination; severe hypokalemia as low as 1.7 m E q / L associated with EKG changes, acidosis, hypercalcemia (14.5 m g m / mL), hypophosphatemia, azotemia, and leucocytosis. She improved with intravenous replacement of her severe salt and water deficits. The cause of her illness was not determined, but she was entirely free of signs of it for lhe next 16 months. On this second admission, she was thin and pale with sunken eyes, but was alert and oriented, complaining of thirst and weakness. Her skin had poor turgor, and the mucous membranes were dry. The rest of the examination was normal. Leucocytosis was present (16,000) with 77% polys, 3% lymphs, 3% monos, and 17 immature polys. The sedimentation rate was normal (16). Serum level of calcium was 10.9, phosphorus was 4.7, urea nitrogen was 41, and creatinine was 1.9. Serum sodium was 134, potassium 4.2, chloride 107, carbon dioxide 9, and glucose 150. She was thought at first to have a psychophysiologic illness manifested by diarrhea. The 16 month disease-free interval reinforced this consideration. However, diet, anticholinergic drugs, and diphenoxy hydrochloride were unsuccessful. Stool volumes increased to 8 to 12 L per day though vomiting subsided. Intravenous requirements went up to 500 m L / h r and 350 mEq K + per day. Oral and intravenous potassium and bicarbonate supplements barely kept up with the losses such that the serum potassium was often <2.0 and bicarbonate was as low as 5. Azotemia increased into the 70s, but the creatinine remained near normal. There was hypercalcemia and hypocalcemia. Hemoglobin
Journal of Pediatric Surgery, Vol 21, No 11 (November). 1986: pp 983-985
Fig 1. ERCP study showing splaying of distal pancreatic ducts suggesting a mass. levels dropped to 6.4, requiring six transfusions. Central venous alimentation was administered for 2 weeks. Dexamethasone, 8 mg per day, was begun 6 weeks after admission when the possibility of a vasoactive intestinal polypeptide (VIP) secreting tumor was again considered, and stool volume decreased to over 4 L per day. Serum vasoactive intestinal polypeptide was 2,150 p g / m L (normal 6 to 36 p g / m L ) 6 weeks after admission (G.I. Hormones Laboratory, Inter Science Institute, Los Angeles, Calif). Serum gastrin was normal. Endoscopic retrograde cholangiographic pancreatography revealed splaying and distortion of the distal ducts of the tail of the pancreas compatible with tumor (Fig I ).
From the Departments of Surgical Education, Pediatrics, and Pathology, Overlook Hospital, Summit, N J; and Columbia University, College of Physicians and Surgeons, New York. "fDeceased. Address reprint requests to Richard W. Brenner, MD, Department of Surgical Education, Overlook Hospital, 193 Morris Ave Summit, NJ 07901. fe3 1986 by Grune & Stratton, Inc. 0022-3468/86/2111-0029503.00/0
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Fig 2.
BRENNER ET AL
Gross photo of cut surface of tumor in tail of pancreas.
Note portion of tumor extending through pancreatic duct in region of normal pancreas (arrow).
Surgery revealed a single 6 • 5 cm lobulated tumor of the pancreatic tail and body firmly attached to the spleen. There was a large gallbladder. The liver was normal and no metastatic deposits were found. Eighty-five percent distal pancreatectomy and splenectomy were done after a lesser resection (70%) showed apparent tumor growth down the main pancreatic duct near to the first line of resection. After final resection the only remaining pancreas (to the right of the superior mesenteric vessels) was free of tumor. Microscopic examination revealed a tumor of islet cells (Fig 2). Because the tumor was found in one of 25 parasplenic lymph nodes and also in a small pancreatic vein, the diagnosis was islet cell carcinoma (Fig 3). Her postoperative course was marked by rapid disappearance of acidosis (pH 7.15 before operation and pH 7.35 eight hours after operation) and by total cessation of the diarrhea. Upper gastrointestinal hemorrhage occurred on the seventh day requiring four transfusions. Serum V1P was normal on the seventh day (12 pg/mL). The tumor contained 2,500 mg of VIP per gram of tumor. There were normal levels of gastric inhibitory polypeptide, pancreatic polypeptide, and secretin in the tumor. She was discharged on the 19th day. Antipneumococcal vaccine had been given, and she had begun long-term oral penicillin. Four, 10, 20, and 36 months after removal, properly harvested VIP levels were normal (36 pg/mL), and there has been no diarrhea or any other symptoms and no evidence for recurrent tumor. DISCUSSION T h e active a g e n t associated with the w a t e r y diarr h e a s y n d r o m e ( p a n c r e a t i c cholera or the V e r n e r M o r r i s o n s y n d r o m e ) is likely the vasoactive i n t e s t i n a l p o l y p e p t i d e first isolated from porcine i n t e s t i n e by S a i d a n d M u t t in 1970. 8 T h e v a l u e of V1P as a t u m o r m a r k e r has b e c o m e well established. Its biologic prop-
Fig 3. Histologic appearance of tumor with solid group pattern of relatively uniform cells surrounding small vascular spaces typical of islet cell tumor.
erties i n c l u d e s t i m u l a t i o n of the a d e n y l cyclase s y s t e m in i n t e s t i n a l m u c o s a l cells t h a t results in p r o f o u n d i n t e s t i n a l secretion of fluid, electrolytes, a n d protein; s t i m u l a t i o n of i n t e s t i n a l motility; v a s o d i l a t i o n ; i n h i b i tion of b a s a l gastric a n d acid secretion not r e f r a c t o r y to h i s t a m i n e s t i m u l a t i o n ; r e s e m b l a n c e to g l u c a g o n in c a u s i n g h y p e r g l y c e m i a (30% as efficient); a n d the s t i m u l a t i o n of glycogenolysis as well as the release of p a n c r e a t i c insulin9; h y p e r c a l c e m i a ; s t i m u l a t i o n of excess p a n c r e a t i c fluid a n d r e l a x a t i o n of the g a l l b l a d der wall. ~~ H e r V I P levels in the s e r u m a n d in the t u m o r were a m o n g the highest t h e n recorded in this l a b o r a t o r y ( I n t e r Science). T h e disease-free i n t e r v a l of 16 m o n t h s is u n e x plained. T h e initial 6-week illness was a l m o s t as severe as the second episode b u t d i s a p p e a r e d w i t h o u t specific t r e a t m e n t . N o histologic t u m o r necrosis was found. T h i s is the first such v i p o m a f o u n d by E R C P p u b l i s h e d in the literature.
REFERENCES 1. Verner JV, Morrison AB: Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med 25:374378, 1958
2. Graham DY, Johnson CE, Ventlif PS, et al: Islet cell carcinoma, pancreatic cholera, and vasoactive intestinal polypeptide. Ann Intern Med 83:732 735, 1975
PANCREATIC VIPOMA
3. Said SI, Faloona GR: Elevated plasma and tissue levels of vasoactive intestinal polypeptide in the watery diarrhea syndrome due to pancreatic, bronchogenic and other tumors. N Engl J Med 293:155-160, 1975 4. Gold RP, Black T J, Rotterdam H, et al: Radiologic and pathologic WHDA syndrome. Am J Rad 127:397-401, 1976 5. Taylor AR, Chulajatad R, Jones DH, et al: Adrenal tumor secreting vasoactive intestinal peptide and noradrenaline. Anesthesia 32:1012 1016, 1977 6. Swift PG, Bloom SR, Harris F: Watery diarrhea and ganglioneuroma with secretion of vasoactive intestinal peptide. Arch Dis Child 50:896-899, 1975
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7. Schein PS, Delellis RA, Kahn CR, et al: Islet cell tumors: Current concepts and management. Ann Intern Med 79:239-257, 1973 8. Said SI, Mutt V: Polypeptide with broad biological activity: Isolation from small intestine. Science 169:1712-1218, 1970 9. Mutt V, Said SI: Structure of porcine vasoactive intestinal octacosapeptide: Amino acid sequence, use of kallikrein in each determination. Eur J Biochem 42:581-589, 1974 10. Zollinger RM, Mazzaferri EL: Tumors of the islets of Langerhans. Adv Surg 10:137 176, 1976
N T H E PAST three decades, reports have appeared of the association of non-beta islet cell adenoma or carcinoma of the pancreas? 4 tumors of the adrenal glands, 5 neural crest 6 and bronchus? and hyperplasia of the pancreatic islets in patients who have a syndrome combining severe water- and protein-losing diarrhea and hypokalemia with or without gastric achlorhydria. This constellation has also been named pancreatic cholera and most recently vipoma and the watery diarrhea syndrome.
I
CASE REPORT A.N., a 15-year-old white female, was admitted with two days of diarrhea up to ten times a day and vomiting. Similar massive secretory diarrhea had occurred over a 6-week period l t/2 years before. Diagnostic studies then did not detect either bowel disease or endocrine abnormality. There was a large normal gallbladder (by ultrasound), which compressed the hepatic flexure during barium enema examination; severe hypokalemia as low as 1.7 m E q / L associated with EKG changes, acidosis, hypercalcemia (14.5 m g m / mL), hypophosphatemia, azotemia, and leucocytosis. She improved with intravenous replacement of her severe salt and water deficits. The cause of her illness was not determined, but she was entirely free of signs of it for lhe next 16 months. On this second admission, she was thin and pale with sunken eyes, but was alert and oriented, complaining of thirst and weakness. Her skin had poor turgor, and the mucous membranes were dry. The rest of the examination was normal. Leucocytosis was present (16,000) with 77% polys, 3% lymphs, 3% monos, and 17 immature polys. The sedimentation rate was normal (16). Serum level of calcium was 10.9, phosphorus was 4.7, urea nitrogen was 41, and creatinine was 1.9. Serum sodium was 134, potassium 4.2, chloride 107, carbon dioxide 9, and glucose 150. She was thought at first to have a psychophysiologic illness manifested by diarrhea. The 16 month disease-free interval reinforced this consideration. However, diet, anticholinergic drugs, and diphenoxy hydrochloride were unsuccessful. Stool volumes increased to 8 to 12 L per day though vomiting subsided. Intravenous requirements went up to 500 m L / h r and 350 mEq K + per day. Oral and intravenous potassium and bicarbonate supplements barely kept up with the losses such that the serum potassium was often <2.0 and bicarbonate was as low as 5. Azotemia increased into the 70s, but the creatinine remained near normal. There was hypercalcemia and hypocalcemia. Hemoglobin
Journal of Pediatric Surgery, Vol 21, No 11 (November). 1986: pp 983-985
Fig 1. ERCP study showing splaying of distal pancreatic ducts suggesting a mass. levels dropped to 6.4, requiring six transfusions. Central venous alimentation was administered for 2 weeks. Dexamethasone, 8 mg per day, was begun 6 weeks after admission when the possibility of a vasoactive intestinal polypeptide (VIP) secreting tumor was again considered, and stool volume decreased to over 4 L per day. Serum vasoactive intestinal polypeptide was 2,150 p g / m L (normal 6 to 36 p g / m L ) 6 weeks after admission (G.I. Hormones Laboratory, Inter Science Institute, Los Angeles, Calif). Serum gastrin was normal. Endoscopic retrograde cholangiographic pancreatography revealed splaying and distortion of the distal ducts of the tail of the pancreas compatible with tumor (Fig I ).
From the Departments of Surgical Education, Pediatrics, and Pathology, Overlook Hospital, Summit, N J; and Columbia University, College of Physicians and Surgeons, New York. "fDeceased. Address reprint requests to Richard W. Brenner, MD, Department of Surgical Education, Overlook Hospital, 193 Morris Ave Summit, NJ 07901. fe3 1986 by Grune & Stratton, Inc. 0022-3468/86/2111-0029503.00/0
983
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Fig 2.
BRENNER ET AL
Gross photo of cut surface of tumor in tail of pancreas.
Note portion of tumor extending through pancreatic duct in region of normal pancreas (arrow).
Surgery revealed a single 6 • 5 cm lobulated tumor of the pancreatic tail and body firmly attached to the spleen. There was a large gallbladder. The liver was normal and no metastatic deposits were found. Eighty-five percent distal pancreatectomy and splenectomy were done after a lesser resection (70%) showed apparent tumor growth down the main pancreatic duct near to the first line of resection. After final resection the only remaining pancreas (to the right of the superior mesenteric vessels) was free of tumor. Microscopic examination revealed a tumor of islet cells (Fig 2). Because the tumor was found in one of 25 parasplenic lymph nodes and also in a small pancreatic vein, the diagnosis was islet cell carcinoma (Fig 3). Her postoperative course was marked by rapid disappearance of acidosis (pH 7.15 before operation and pH 7.35 eight hours after operation) and by total cessation of the diarrhea. Upper gastrointestinal hemorrhage occurred on the seventh day requiring four transfusions. Serum V1P was normal on the seventh day (12 pg/mL). The tumor contained 2,500 mg of VIP per gram of tumor. There were normal levels of gastric inhibitory polypeptide, pancreatic polypeptide, and secretin in the tumor. She was discharged on the 19th day. Antipneumococcal vaccine had been given, and she had begun long-term oral penicillin. Four, 10, 20, and 36 months after removal, properly harvested VIP levels were normal (36 pg/mL), and there has been no diarrhea or any other symptoms and no evidence for recurrent tumor. DISCUSSION T h e active a g e n t associated with the w a t e r y diarr h e a s y n d r o m e ( p a n c r e a t i c cholera or the V e r n e r M o r r i s o n s y n d r o m e ) is likely the vasoactive i n t e s t i n a l p o l y p e p t i d e first isolated from porcine i n t e s t i n e by S a i d a n d M u t t in 1970. 8 T h e v a l u e of V1P as a t u m o r m a r k e r has b e c o m e well established. Its biologic prop-
Fig 3. Histologic appearance of tumor with solid group pattern of relatively uniform cells surrounding small vascular spaces typical of islet cell tumor.
erties i n c l u d e s t i m u l a t i o n of the a d e n y l cyclase s y s t e m in i n t e s t i n a l m u c o s a l cells t h a t results in p r o f o u n d i n t e s t i n a l secretion of fluid, electrolytes, a n d protein; s t i m u l a t i o n of i n t e s t i n a l motility; v a s o d i l a t i o n ; i n h i b i tion of b a s a l gastric a n d acid secretion not r e f r a c t o r y to h i s t a m i n e s t i m u l a t i o n ; r e s e m b l a n c e to g l u c a g o n in c a u s i n g h y p e r g l y c e m i a (30% as efficient); a n d the s t i m u l a t i o n of glycogenolysis as well as the release of p a n c r e a t i c insulin9; h y p e r c a l c e m i a ; s t i m u l a t i o n of excess p a n c r e a t i c fluid a n d r e l a x a t i o n of the g a l l b l a d der wall. ~~ H e r V I P levels in the s e r u m a n d in the t u m o r were a m o n g the highest t h e n recorded in this l a b o r a t o r y ( I n t e r Science). T h e disease-free i n t e r v a l of 16 m o n t h s is u n e x plained. T h e initial 6-week illness was a l m o s t as severe as the second episode b u t d i s a p p e a r e d w i t h o u t specific t r e a t m e n t . N o histologic t u m o r necrosis was found. T h i s is the first such v i p o m a f o u n d by E R C P p u b l i s h e d in the literature.
REFERENCES 1. Verner JV, Morrison AB: Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med 25:374378, 1958
2. Graham DY, Johnson CE, Ventlif PS, et al: Islet cell carcinoma, pancreatic cholera, and vasoactive intestinal polypeptide. Ann Intern Med 83:732 735, 1975
PANCREATIC VIPOMA
3. Said SI, Faloona GR: Elevated plasma and tissue levels of vasoactive intestinal polypeptide in the watery diarrhea syndrome due to pancreatic, bronchogenic and other tumors. N Engl J Med 293:155-160, 1975 4. Gold RP, Black T J, Rotterdam H, et al: Radiologic and pathologic WHDA syndrome. Am J Rad 127:397-401, 1976 5. Taylor AR, Chulajatad R, Jones DH, et al: Adrenal tumor secreting vasoactive intestinal peptide and noradrenaline. Anesthesia 32:1012 1016, 1977 6. Swift PG, Bloom SR, Harris F: Watery diarrhea and ganglioneuroma with secretion of vasoactive intestinal peptide. Arch Dis Child 50:896-899, 1975
985
7. Schein PS, Delellis RA, Kahn CR, et al: Islet cell tumors: Current concepts and management. Ann Intern Med 79:239-257, 1973 8. Said SI, Mutt V: Polypeptide with broad biological activity: Isolation from small intestine. Science 169:1712-1218, 1970 9. Mutt V, Said SI: Structure of porcine vasoactive intestinal octacosapeptide: Amino acid sequence, use of kallikrein in each determination. Eur J Biochem 42:581-589, 1974 10. Zollinger RM, Mazzaferri EL: Tumors of the islets of Langerhans. Adv Surg 10:137 176, 1976