Pheochromocytoma Producing Vasoactive Intestinal Peptide
2002; Elsevier BV; Volume: 77; Issue: 1 Linguagem: Inglês
10.4065/77.1.97
ISSN1942-5546
AutoresStephen L. Smith, A.L. Jackson Slappy, Thomas Peter Fox, James S. Scolapio,
Tópico(s)Lung Cancer Research Studies
ResumoThe syndrome of watery diarrhea associated with hypokalemia and achlorhydria was originally described in 1958. Subsequently, this syndrome was shown to be caused by a neuroendocrine tumor secreting vasoactive intestinal peptide (VIP), and such tumors are almost always pancreatic in origin. We describe the case of a 78-year-old woman with gradual onset of hypokalemia, watery diarrhea, and weight loss. After a left adrenal mass was discovered, the patient chose medical therapy over surgical intervention. Initially her condition responded, then gradually became refractory to medical therapy. She had elevated levels of VIP, pancreatic polypeptide, dopamine, and vanillylmandelic acid. Subsequently, the patient underwent surgical excision of the mass that was found to be a VIP-producing pheochromocytoma. After surgery her diarrhea subsided, and her electrolytes and affected neuroendocrine hormone levels normalized. The syndrome of watery diarrhea associated with hypokalemia and achlorhydria was originally described in 1958. Subsequently, this syndrome was shown to be caused by a neuroendocrine tumor secreting vasoactive intestinal peptide (VIP), and such tumors are almost always pancreatic in origin. We describe the case of a 78-year-old woman with gradual onset of hypokalemia, watery diarrhea, and weight loss. After a left adrenal mass was discovered, the patient chose medical therapy over surgical intervention. Initially her condition responded, then gradually became refractory to medical therapy. She had elevated levels of VIP, pancreatic polypeptide, dopamine, and vanillylmandelic acid. Subsequently, the patient underwent surgical excision of the mass that was found to be a VIP-producing pheochromocytoma. After surgery her diarrhea subsided, and her electrolytes and affected neuroendocrine hormone levels normalized. Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide that may cause secretory diarrhea by stimulating adenylate cyclase production. This in turn causes intestinal secretion of water and electrolytes.1Alam MJ Chronic refractory diarrhoea: a manifestation of endocrine disorders.Dig Dis. 1994; 12: 46-61Crossref PubMed Scopus (5) Google Scholar Verner and Morrison2Verner JV Morrison AB Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia.Am J Med. 1958; 25: 374-380Abstract Full Text PDF PubMed Scopus (388) Google Scholar first described the syndrome of watery diarrhea associated with hypokalemia and achlorhydria (WDHA) in 1958. The first description of a nonpancreatic tumor producing VIP was a retroperitoneal ganglioneuroma reported by Fausa et al3Fausa O Fretheim B Elgjo K Semb L Gjone E Intractable watery diarrhoea, hypokalaemia, and achlorhydria associated with non-pancreatic retroperitoneal neurogenous tumour containing vasoactive intestinal peptide (V.I.P.).Scand J Gastroenterol. 1973; 8: 713-717PubMed Google Scholar in 1973. Loehry et al4Loehry CA Kingham JG Whorwell PJ Watery diarrhoea and hypokalaemia associated with a phaeochromocytoma.Postgrad Med J. 1975; 51: 416-419Crossref PubMed Scopus (22) Google Scholar first reported an association between the WDHA syndrome and a pheochromocytoma in 1975. Since that time only a few nonpancreatic tumors associated with the WDHA syndrome have been reported.5Sackel SG Manson JE Harawi SJ Burakoff R Watery diarrhea syndrome due to an adrenal pheochromocytoma secreting vasoactive intestinal polypeptide.Dig Dis Sci. 1985; 30: 1201-1207Crossref PubMed Scopus (30) Google Scholar, 6Bloom SR Polak JM Pearse AG Vasoactive intestinal peptide and watery-diarrhoea syndrome.Lancet. 1973; 2: 14-16Abstract PubMed Scopus (340) Google Scholar, 7Trump DL Livingston JN Baylin SB Watery diarrhea syndrome in an adult with ganglioneuroma-pheochromocytoma: identificationof vasoactive intestinal peptide, calcitonin, and catecholamines and assessment of their biologic activity.Cancer. 1977; 40: 1526-1532Crossref PubMed Scopus (67) Google Scholar, 8Cooperman AM Desantis D Winkelman E Farmer R Eversman J Said S Watery diarrhea syndrome: two unusual cases and further evidence that VIP is a humoral mediator.Ann Surg. 1978; 187: 325-328Crossref PubMed Scopus (27) Google Scholar, 9Nigawara K Suzuki T Tazawa H et al.A case of recurrent malignant pheochromocytoma complicated by watery diarrhea, hypokalemia, achlorhydria syndrome.J Clin Endocrinol Metab. 1987; 65: 1053-1056Crossref PubMed Scopus (21) Google Scholar, 10Matta MK Prorok JJ Trimpi HD Sheets JA Stasik Jr, JJ Khubchandani IT WDHA syndrome caused by pheochromocytoma: report of a case.Dis Colon Rectum. 1978; 21: 297-301Crossref PubMed Scopus (13) Google Scholar, 11Bernard P Lebras J Pradel J Viguier AC Curet P Grellet J Angiographic exploration of a case of adrenal APUD adenoma secreting three hormones: VIP, catecholamines, and somatostatin [in French].J Radiol. 1980; 61: 121-124PubMed Google Scholar, 12Viale G Dell'Orto P Moro E Cozzaglio L Coggi G Vasoactive intestinal polypeptide-, somatostatin-, and calcitonin-producing adrenal pheochromocytoma associated with the watery diarrhea (WDHH) syndrome: first case report with immunohistochemical findings.Cancer. 1985; 55: 1099-1106Crossref PubMed Scopus (62) Google Scholar, 13Hassoun J Monges G Giraud P et al.Immunohistochemical study of pheochromocytomas: an investigation of methionine-enkephalin, vasoactive intestinal peptide, somatostatin, corticotropin, beta-endorphin, and calcitonin in 16 tumors.Am J Pathol. 1984; 114: 56-63PubMed Google Scholar, 14Contreras LN Budd D Yen TS Thomas C Tyrrell JB Adrenal ganglioneuroma-pheochromocytoma secreting vasoactive intestinal polypeptide.West J Med. 1991; 154: 334-337PubMed Google Scholar We describe a woman who presented with chronic diarrhea, hypokalemia, and a left adrenal mass. A left adrenal VIP-producing pheochromocytoma was resected successfully. A 78-year-old woman was found to be hypokalemic in August 1991, was hospitalized, and was treated with potassium replacement. The etiology of her hypokalemia was not established at that time. In August 1992, she was hospitalized because of a low serum potassium level, with no definitive diagnosis. In October 1993, she experienced watery diarrhea. The diarrhea continued for 2 months, at which time she was hospitalized. Findings on an upper gastrointestinal barium swallow examination with small bowel follow-through, barium enema, esophagogastroduodenoscopy, and colonoscopy were normal. Computed tomography (CT) of the abdomen revealed a left suprarenal mass (6.5 cm). The patient refused a recommendation of surgical treatment and began a trial of cholestyramine and octreotide, with some improvement. The patient presented to Mayo Clinic, Jacksonville, Fla, in early January 1994 for evaluation of her condition and treatment plan. She admitted to non-foul-smelling watery stools 8 to 10 times a day that were unaffected by eating habits. She denied having a loss of appetite but admitted to a weight loss of approximately 9.0 kg over the previous year. Her serum VIP level (reference range shown parenthetically) was 510 pg/mL (0-75 pg/mL) and serum pancreatic polypeptide value was 397 pg/mL (0-332 pg/mL). Results of 24-hour urinary studies were as follows: volume, 300 mL; dopamine, 509 μg/24 h (65-400 μg/24 h); epinephrine, 5.2 μg/24 h (0-20 μg/24 h); norepinephrine, 52 μg/24 h (15-80 μg/24 h); and creatinine, 393 mg/24 h (0-80 mg/24 h). Studies of stool specimens revealed a sodium level of 71 mEq/24 h (<20 mEq/24 h), potassium level of 88 mEq/24 h (<30 mEq/24 h), and mass of 1407 g/48 h (<200 g/24 h). In light of the patient's history and laboratory results, surgical removal of the adrenal mass was recommended; however, she again refused, wishing to avoid surgery “at all costs.” In September 1994, the patient was transferred to St Luke's Hospital, Jacksonville, Fla, because of chronic refractory diarrhea, hypokalemia, and dehydration. In the 2 months preceding this admission, the patient experienced worsening diarrhea and further weight loss of 13.6 kg. Her medical history included type 2 diabetes mellitus, longstanding hypertension, peripheral vascular disease, a cerebrovascular accident, and chronic obstructive pulmonary disease. Her surgical history was notable for a left carotid endarterectomy in June 1993. She denied any tobacco or alcohol use. Family history revealed no other endocrinopathies. Her medications included chlorpropamide, cholestyramine, octreotide, and potassium chloride. On admission the patient's vital signs were a temperature of 36.6°C, blood pressure of 130/70 mm Hg, heart rate of 72 beats/min, respirations of 18/min, and weight of 68.0 kg. Physical examination findings were otherwise unremarkable. Abnormal pertinent laboratory values were as follows: hemoglobin, 10.9 g/dL (12.0-15.5 g/dL); hematocrit, 32.7% (34.9%-44.5%); white blood cells, 10.9 × 109/L (3.5-10.5 × 109/L); neutrophils, 93.7% (44.4%-70.9%); lymphocytes, 3.5% (17.8%-41.5%); monocytes, 1.8% (4.7%-14.8%); eosinophils, 0.3% (0.8%-2.2%); pH, 7.22 (7.35-7.45); base excess, 12.6 mmol/L (-2.0 to +2.0 mmol/L); potassium, 2.9 mEq/L (3.6-4.8 mEq/L); bicarbonate, 12 mEq/L (22-29 mEq/L); blood urea nitrogen, 43 mg/dL (6-21 mg/dL); glucose, 240 mg/dL (70-100 mg/dL); and serum VIP, 594 pg/mL. Findings on 24-hour urinary studies disclosed a volume of 1300 mL, dopamine level of 840 μg/24 h, epinephrine level of 2.7 μg/24 h, norepinephrine level of 27 μg/24 h, and vanillylmandelic acid level of 17.0 μg/24 h (<8.0 μg/24 h). Stool microbiology studies were negative for Clostridium difficile toxin A, ova, and parasites. Findings on chest radiography were normal, and abdominal CT with thin cuts through the pancreas revealed normal findings except for a 6.5-cm lesion with a ringlike calcification in the left adrenal gland. Abdominal ultrasonography showed no lesions in the pancreas. Because of worsening symptoms despite multidrug therapy, the patient decided to undergo surgery. Preoperatively, she was rehydrated, electrolyte abnormalities were corrected, and a course of phenoxybenzamine treatment was completed. Findings on intraoperative ultrasonography and bimanual palpation of the pancreas disclosed no pancreatic lesion. The left adrenal gland was resected transabdominally through a subcostal incision. Grossly, the redpink homogeneous 6-cm tumor had a necrotic center (Figure 1). After dichromate was applied to the specimen, portions became brown. These gross characteristics are typical of pheochromocytoma. Microscopically, large polygonal cells with granular cytoplasm were clustered in small groups invested by a fine fibrovascular stroma. Tumor cells showed prominent nucleoli (Figure 2) and were positive for VIP by immunohistochemistry.Figure 2Left, Sheets of tumor cells are divided and packaged by a thin fibrovascular stroma (arrows), creating a typical “zellballen” appearance of a paraganglioma (hematoxylineosin, original magnification x100). Right, Higher power examination reveals variably sized nuclei with some chromatin clearing, tiny nucleoli, and occasional multinucleation. Granular cytoplasm is present in all tumor cells (hematoxylineosin, original magnification x400).View Large Image Figure ViewerDownload (PPT) The patient tolerated her operation well and had an uneventful postoperative course. Postoperatively, her diarrhea and hypokalemic metabolic acidosis resolved. Abnormal postoperative test results were as follows: hemoglobin, 9.0 g/dL; hematocrit, 27.1%; PO2, 225.8 mm Hg (80-100 mm Hg); base excess, 1.6 mmol/L; and bicarbonate, 32 mEq/L. Results of 24-hour urinary studies were as follows: volume, 1700 mL; dopamine, 45 μg/24 h; epinephrine, 1.4 μg/24 h; norepinephrine, 14 μg/24 h; metanephrine, 1.1 mg/24 h (0-1.3 mg/24 h); and vanillylmandelic acid, 3.5 μg/24 h. The patient was discharged home on the fifth day after surgery. Postoperative levels of the patient's serum VIP normalized (27 pg/mL) within 4 weeks. At follow-up 24 months after surgery, the patient was well and asymptomatic. VIP-secreting tumors (VIPomas) are a rare cause of secretory diarrhea, defined as fecal water greater than 500 mL/d. The stool is typically isotonic, and diarrhea persists despite fasting. Common causes of chronic refractory diarrhea of endocrine etiology include adrenal insufficiency, abnormal thyroid function, and diabetes. Less frequent causes are gastrinoma, VIPoma, villous adenoma, medullary thyroid carcinoma, ganglioneuroma, pheochromocytoma, carcinoid tumor, and glucagonoma. Clinical symptoms commonly found with the VIPoma syndrome include secretory diarrhea, dehydration, weight loss, abdominal cramps, and flushing. Characteristic laboratory abnormalities include hypokalemia, hypochlorhydria, hypercalcemia, hyperglycemia, and metabolic acidosis secondary to bicarbonate secretion from the intestine.1Alam MJ Chronic refractory diarrhoea: a manifestation of endocrine disorders.Dig Dis. 1994; 12: 46-61Crossref PubMed Scopus (5) Google Scholar, 3Fausa O Fretheim B Elgjo K Semb L Gjone E Intractable watery diarrhoea, hypokalaemia, and achlorhydria associated with non-pancreatic retroperitoneal neurogenous tumour containing vasoactive intestinal peptide (V.I.P.).Scand J Gastroenterol. 1973; 8: 713-717PubMed Google Scholar, 4Loehry CA Kingham JG Whorwell PJ Watery diarrhoea and hypokalaemia associated with a phaeochromocytoma.Postgrad Med J. 1975; 51: 416-419Crossref PubMed Scopus (22) Google Scholar, 5Sackel SG Manson JE Harawi SJ Burakoff R Watery diarrhea syndrome due to an adrenal pheochromocytoma secreting vasoactive intestinal polypeptide.Dig Dis Sci. 1985; 30: 1201-1207Crossref PubMed Scopus (30) Google Scholar The first description of a nonpancreatic tumor producing the WDHA syndrome was a retroperitoneal ganglioneuroma reported by Fausa et al3Fausa O Fretheim B Elgjo K Semb L Gjone E Intractable watery diarrhoea, hypokalaemia, and achlorhydria associated with non-pancreatic retroperitoneal neurogenous tumour containing vasoactive intestinal peptide (V.I.P.).Scand J Gastroenterol. 1973; 8: 713-717PubMed Google Scholar in 1973. Since then other nonpancreatic tumors producing VIP have been reported, including bronchogenic carcinomas, pheochromocytomas, ganglioneuromas, and a rare mastocytoma.4Loehry CA Kingham JG Whorwell PJ Watery diarrhoea and hypokalaemia associated with a phaeochromocytoma.Postgrad Med J. 1975; 51: 416-419Crossref PubMed Scopus (22) Google Scholar, 5Sackel SG Manson JE Harawi SJ Burakoff R Watery diarrhea syndrome due to an adrenal pheochromocytoma secreting vasoactive intestinal polypeptide.Dig Dis Sci. 1985; 30: 1201-1207Crossref PubMed Scopus (30) Google Scholar, 6Bloom SR Polak JM Pearse AG Vasoactive intestinal peptide and watery-diarrhoea syndrome.Lancet. 1973; 2: 14-16Abstract PubMed Scopus (340) Google Scholar, 7Trump DL Livingston JN Baylin SB Watery diarrhea syndrome in an adult with ganglioneuroma-pheochromocytoma: identificationof vasoactive intestinal peptide, calcitonin, and catecholamines and assessment of their biologic activity.Cancer. 1977; 40: 1526-1532Crossref PubMed Scopus (67) Google Scholar, 8Cooperman AM Desantis D Winkelman E Farmer R Eversman J Said S Watery diarrhea syndrome: two unusual cases and further evidence that VIP is a humoral mediator.Ann Surg. 1978; 187: 325-328Crossref PubMed Scopus (27) Google Scholar, 9Nigawara K Suzuki T Tazawa H et al.A case of recurrent malignant pheochromocytoma complicated by watery diarrhea, hypokalemia, achlorhydria syndrome.J Clin Endocrinol Metab. 1987; 65: 1053-1056Crossref PubMed Scopus (21) Google Scholar, 10Matta MK Prorok JJ Trimpi HD Sheets JA Stasik Jr, JJ Khubchandani IT WDHA syndrome caused by pheochromocytoma: report of a case.Dis Colon Rectum. 1978; 21: 297-301Crossref PubMed Scopus (13) Google Scholar, 11Bernard P Lebras J Pradel J Viguier AC Curet P Grellet J Angiographic exploration of a case of adrenal APUD adenoma secreting three hormones: VIP, catecholamines, and somatostatin [in French].J Radiol. 1980; 61: 121-124PubMed Google Scholar, 12Viale G Dell'Orto P Moro E Cozzaglio L Coggi G Vasoactive intestinal polypeptide-, somatostatin-, and calcitonin-producing adrenal pheochromocytoma associated with the watery diarrhea (WDHH) syndrome: first case report with immunohistochemical findings.Cancer. 1985; 55: 1099-1106Crossref PubMed Scopus (62) Google Scholar, 13Hassoun J Monges G Giraud P et al.Immunohistochemical study of pheochromocytomas: an investigation of methionine-enkephalin, vasoactive intestinal peptide, somatostatin, corticotropin, beta-endorphin, and calcitonin in 16 tumors.Am J Pathol. 1984; 114: 56-63PubMed Google Scholar, 14Contreras LN Budd D Yen TS Thomas C Tyrrell JB Adrenal ganglioneuroma-pheochromocytoma secreting vasoactive intestinal polypeptide.West J Med. 1991; 154: 334-337PubMed Google Scholar Rarely, VIPomas can be part of the multiple endocrine neoplasia type 1 syndrome consisting of the triad of a functioning endocrine pancreatic tumor, parathyroid tumor, and pituitary tumor.15Majewski JT Wilson SD The MEA-I syndrome: an all or none phenomenon?.Surgery. 1979; 86: 475-484PubMed Google Scholar Hypersecretion of hormones other than VIP,16Herrera MF Stone E Deitel M Asa SL Pheochromocytoma producing multiple vasoactive peptides.Arch Surg. 1992; 127: 105-108Crossref PubMed Scopus (30) Google Scholar such as erythropoietin,17Jacobs P Wood L Recurrent benign erythropoietin-secreting pheochromocytomas.Am J Med. 1994; 97: 307-308Abstract Full Text PDF PubMed Scopus (5) Google Scholar steroids,18Landsberg L Young JB Catecholamines and the adrenal medulla.in: Wilson JD Foster DW Williams Textbook of Endocrinology. 8th ed. WB Saunders Co, Philadelphia, Pa1992: 669Google Scholar or calcitonin,19Heath III, H Edis AJ Pheochromocytoma associated with hypercalcemia and ectopic secretion of calcitonin.Ann Intern Med. 1979; 91: 208-210Crossref PubMed Scopus (52) Google Scholar has been reported in association with pheochromocytomas and paragangliomas, creating nonclassic signs, symptoms, and presentations. Other hormones reported to be secreted include parathyroid hormone-related peptide, serotonin, gastrin, atrial natriuretic peptide, somatostatin, renin, and angiotensin-converting enzyme.20Manger WM Gifford Jr, RW Pheochromocytoma: current diagnosis and management.Cleve Clin J Med. 1993; 60: 365-378Crossref PubMed Scopus (62) Google Scholar, 21Mune T Katakami H Kato Y Yasuda K Matsukura S Miura K Production and secretion of parathyroid hormone-related protein in pheochromocytoma: participation of an alpha-adrenergic mechanism.J Clin Endocrinol Metab. 1993; 76: 757-762Crossref PubMed Scopus (37) Google Scholar, 22Sheps SG Jiang N-S Klee GG van Heerden JA Recent developments in the diagnosis and treatment of pheochromocytoma.Mayo Clin Proc. 1990; 65: 88-95Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar Fried et al23Fried G Wikstrom LM Hoog A et al.Multiple neuropeptide immunoreactivities in a renin-producing human paraganglioma.Cancer. 1994; 74: 142-151Crossref PubMed Scopus (18) Google Scholar documented the presence of enkephalin, galanin, substance P, and cholecystokinin, as well as high levels of renin in the paraganglioma of a patient. Corticotropin-releasing hormone, growth hormone-releasing hormone, and peptide histidine methionine are present in varying proportions in the extracts of some adrenal pheochromocytomas. In contrast, they are absent in the extracts of extra-adrenal pheochromocytomas.24Sasaki A Yumita S Kimura S Miura Y Yoshinaga K Immunoreactive corticotropin-releasing hormone, growth hormone-releasing hormone, somatostatin, and peptide histidine methionine are present in adrenal pheochromocytomas, but not in extra-adrenal pheochromocytoma.J Clin Endocrinol Metab. 1990; 70: 996-999Crossref PubMed Scopus (31) Google Scholar The diagnosis of a pheochromocytoma is based on the physician's clinical suspicion and the elevated levels of urinary catecholamines and their metabolites. In some patients other hormone levels may also be elevated. Ultrasonography, CT, magnetic resonance imaging, and scintigraphy may help to localize the tumor. If a VIPoma is suspected and no pancreatic mass can be found, ganglioneuroma (especially in children), bronchogenic carcinoma, or adrenal tumors must be excluded. The definitive treatment of VIPomas is surgery. For patients who are not surgical candidates, somatostatin may be successful as short-term therapy for diarrhea; however, rebound diarrhea has been reported.25Koelz A Kraenzlin M Gyr K et al.Escape of the response to a long-acting somatostatin analogue (SMS 201-995) in patients with VIPoma.Gastroenterology. 1987; 92: 527-531PubMed Google Scholar In patients with metastatic disease, chemotherapy with streptozocin and 5-fluorouracil may produce up to a 60% to 70% response rate.26Moertel CG Lefkopoulo M Lipsitz S Hahn RG Klaassen D Streptozocin-doxorubicin, streptozocin-fluorouracil, or chloro-zotocin in the treatment of advanced islet-cell carcinoma.N Engl J Med. 1992; 326: 519-523Crossref PubMed Scopus (805) Google Scholar Our patient had a rare pheochromocytoma secreting VIP that caused the WDHA syndrome. Definitive treatment was surgical removal of the pheochromocytoma that stained positive for VIP at histopathological examination. Postoperatively, the patient's serum VIP level normalized, and she experienced complete remission.
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