Hardeep M. Singh, Senior Fellow, Department of Gastroenterology; Thomas Teller, Chief, Department of Gastroenterology; Karl T. Esrason, Staff Hepatologist, Department of Gastroenterology; Maher A. Abbas, Staff Colorectal Surgeon, Department of Surgery, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA
Hardeep M. Singh, MD
Department of Gastroenterology
Thomas Teller, MD
Department of Gastroenterology
Karl T. Esrason, MD
Department of Gastroenterology
Maher A. Abbas, MD
Staff Colorectal Surgeon
Department of Surgery
Los Angeles Medical Center
Los Angeles, CA
Introduction: Tumors that secrete an excess of vasoactive intestinal peptide (VIP) are known as VIPomas. These rare tumors typically affect the pancreas and are often diagnosed only after they have metastasized. The most common symptom is chronic refractory diarrhea.
Results and discussion: This paper reports an unusual case of a VIPoma in a patient who had an acute presentation, which is a very unusual form of this rare clinical entity. It also provides a review of the literature and discusses the clinical findings and treatment of these lesions.
Conclusion: Conventional imaging mo?dalities may not be sufficient to visualize VIPomas adequately, and somatostatin receptor scintigraphy or endoscopic ultrasonography with biopsy may be necessary to establish the diagnosis. The mainstay of treatment is surgical resection, which often provides immediate relief of symptoms and can be curative when metastases have not occurred.
Pancreatic endocrine tumors (PETs) are rare tumors that vary in their incidence and malignancy potential. Because these tumors grow slowly, they often have an insidious presentation, can be difficult to localize, and are diagnosed usually only after metastases have occurred. Functioning PETs can produce a variety of clinical syndromes, depending on which hormones they secrete. Pancreatic tumors that secrete an excess of vasoactive intestinal peptide (VIP) are classified as VIPomas. The primary symptom of excess VIP secretion is typically chronic refractory diarrhea.
We report the case of a 51-year-old woman with an acute presentation of secretory diarrhea, hypovolemia, hypokalemia, and metabolic acidosis. A tumor secreting VIP and glucagon was found in the tail of the patient's pancreas. She underwent a distal pancreatectomy and splenectomy, with subsequent resolution of her diarrhea and normalization of her serum VIP and glucagon levels. This case demonstrates that VIPoma can occasionally have an acute presentation.
A 51-year-old Japanese woman presented with the abrupt onset of diarrhea and vomiting. She was in her usual state of health until 5 days prior to admission, when she developed acute diarrhea. Her symptoms progressed from 5 loose stools daily to over 10 nonbloody, liquid bowel movements each day. The patient vomited four times per day and noted a pruritic rash on her inner thighs that started 2 days before the onset of her diarrhea. By the time of her admission, the rash had resolved spontaneously.
The patient reported no abdominal pain, weight loss, fevers, chills, or night sweats and noted no other recent episodes of diarrhea. Her medical history was remarkable for depression, endometriosis, and gastroesophageal reflux disease. Her medications included omeprazole, citalopram, and a daily multivitamin. She reported no alcohol or illicit drug use.
On physical examination, the patient was weak, distressed, and dehydrated. She was afebrile but tachycardic. Her mucous membranes were dry. Her abdomen was soft, nontender, and nondistended, with normoactive bowel sounds on auscultation. No abdominal masses, organomegaly, or peripheral lymphadenopathy were noted.
On admission to the hospital, her laboratory results were significant for mild leukocytosis, elevated hematocrit, non?anion-gap metabolic acidosis, elevated aminotransferase levels, and hypokalemia. Stool studies were negative for parasites and bacteria, including . Hepatitis serology indicated distant exposure to hepatitis A. Abdominal ultrasonography to evaluate the liver revealed a 7.5-cm mass in the left upper quadrant. A computed tomography (CT) scan of the abdomen demonstrated a heterogeneously enhancing solid mass arising from the tail of the pancreas (Figure 1).
The patient continued to experience intractable diarrhea, despite the use of lo?peramide (16 mg/day) and diphenoxylate with atropine (6 to 8 tablets daily). Her diarrhea was voluminous and failed to improve with fasting. She remained persistently hypokalemic and acidotic despite aggressive intravenous fluid resuscitation and daily potassium replacement in excess of 200 mEq. An ultrasonography?
guided biopsy revealed an islet cell tumor. Octreotide scanning demonstrated a localized area of uptake in the left upper quadrant, corresponding to the mass observed in the tail of the pancreas on the CT scan (Figure 2). Neuroendocrine markers were remarkable for a serum glucagon level of 397 pg/mL (normal, < 60 pg/mL) and a VIP level above 400 pg/mL (normal, < 50 pg/mL).
On hospital day 13, the patient underwent a distal pancreatectomy and splenectomy. No gross metastatic disease was noted intraoperatively. The patient had an uneventful postoperative course with complete resolution of her diarrhea and normalization of her serum potassium. Histopathologic evaluation revealed a neuroendocrine tumor strongly positive for chromogranin A (Figure 3). A minority of cells stained positively for glucagon, and a moderate number of cells stained positive for VIP (Figure 4). Metastatic neuroendocrine carcinoma was noted in six of seven excised lymph nodes. The margins of the pancreas were free of tumor, and the spleen was normal.
Three weeks postoperatively, the patient's serum potassium and glucose levels were normal (Table). Her serum VIP and glucagon remained normal at 37.7 pg/mL and below 50 pg/mL, respectively. Her serum chromogranin A level was elevated at 120.5 ng/mL (normal, 6 to 39 ng/mL). No baseline level was available. At 3, 6, and 15 months postoperatively, the patient remained asymptomatic with normal VIP and glucagon levels. Her chromogranin A level normalized 6 months after the operation.
Octreotide scanning performed 6 weeks postoperatively revealed no residual tumor or metastatic disease. At 6- and 15-month follow-up, repeat octreotide scans demonstrated the interval development of a small focus of uptake medial to the left renal pelvis and an area of uptake anterolateral to the right hepatic lobe. CT scanning revealed ret?roperitoneal lymphadenopathy consistent with recurrent disease. Twenty months postresection, the patient remains asymptomatic and has declined further workup or intervention.
Pancreatic VIPoma was first described in 1958 by Verner and Morrison in a patient with chronic refractory diarrhea and hypokalemia.1 Synonyms for pancreatic VIPoma include watery diarrhea-hypokalemia-
achlorhydria (WDHA) syndrome, Verner-Morrison syndrome, and pancreatic cholera. VIPoma is exceptionally rare, with an annual reported incidence between 0.2 and 2 cases per million people.2,3 The majority of tumors are malignant, and most patients present with metastatic disease.2-6 VIPomas are slow growing and generally cause symptoms due to their excessive production of VIP, a physiologically active hormone.
Most PETs secrete more than one hormone but, for unknown reasons, patients typically only manifest symptoms attributable to one hormone.2,4,5,7 In patients with VIPoma, the most common manifestations are chronic secretory diarrhea, hypokalemia, and metabolic acidosis.2-4 These tumors may be difficult to localize by conventional radiographic studies. Somatostatin receptor scintigraphy or endoscopic ultrasonography with biopsy may be necessary to establish the diagnosis. Surgery remains the mainstay of treatment for lesions localized to the pancreas and offers the best chance of a cure.2-4,8-10
Our patient's presentation was most consistent with WDHA syndrome be?cause she had the typical symptoms of a large volume of diarrhea, hypovolemia, and refractory hypokalemia. The etiology of her diarrhea was secretory because it was voluminous and failed to improve with fasting. Stool output in patients with VIPomas ranges from 1 L to more than 3 L daily, leading to profound dehydration and acidosis.11,12 Hypokalemia is a universal finding, resulting from fecal loss of potassium and from secondary hyperaldosteronism.2 Acute renal failure resulting from the dehydration caused by WDHA syndrome also has been reported.13
The most common symptoms of VIPoma include diarrhea, dehydration, weight loss, hypokalemia, and achlorhydria. In a series of 31 patients reported by Peng and colleagues, all patients had diarrhea, significant weight loss, and dehydration.3 Of these patients, 68% had hypokalemia and 64% had achlorhydria.3 In a review of 241 patients by Soga and colleagues, diarrhea was noted in all patients, hypokalemia in 89%, achlorhydria in 43%, and weight loss in 36%.4 Our patient reported no weight loss and did not have achlorhydria while in the hospital. She did exhibit mild glucose intolerance, with her fasting blood sugar ranging from 130 to 150 mg/dL. Hyperglycemia was also noted in 28% of patients in Peng and colleagues' review.3 This is thought to be secondary to VIP's stimulation of hepatic glycogenolysis.2
Our case diverges from the typical description of WDHA syndrome in the acuity of our patient's symptoms. VIPomas are slow-growing, and previously reported cases consistently describe a slowly progressing constellation of associated symptoms.3,14 In many cases, mild hypokalemia and hypoglycemia are noted incidentally on laboratory tests. Initially, diarrhea is often mild and well-controlled with antidiarrheal medications. It is the chronicity and progression of these symptoms over time that prompts a workup. Our patient had no history of hypokalemia, hyperglycemia, weight loss, or diarrhea prior to the week of her presentation. At baseline, she had one or two formed stools per day. Within a 5-day period, she progressed to over 10 bowel movements daily, which resulted in profound dehydration, orthostasis, and hypokalemia. In reviewing other case reports of patients with WDHA syndrome, we did not find any who noted such an acute presentation.
Malignancy of PETs varies, depending on the type of tumor, and is defined by the presence of tumor invasion, metastatic spread, or both. More than 60% of VIPomas and glucagonomas are malignant at the time of diagnosis, with the majority invading the liver and local lymph nodes.2-6 Our patient had evidence of lymph node involvement at the time of her resection. She also had an elevation in her aminotransferase levels, which has persisted chronically. Her workup, including hepatitis serology and metabolic studies, was negative. Given the possibility of metastatic disease, we recommended that she undergo a liver biopsy, but she declined.
Surgical resection can offer immediate improvement in symptoms and may increase survival. Matthews and colleagues reported the surgical outcome of 20 patients with functioning PETs.10 Of these patients, 90% had complete resolution of their symptoms and normalization of their neuroendocrine markers postoperatively. Two-year survival was 60%. Because of the slow-growing nature of these tumors, surgery may be considered for patients with metastatic disease. In a review by Sarmiento and colleagues, 170 patients with metastatic PETs to the liver underwent surgical debulking.9 Of these patients, 96% showed improvement in their symptoms after surgery, and the 5-year survival was 61%. Although symptoms recurred in over half of these patients within 5 years, the symptoms tended to be easier to control with medical therapy.
Somatostatin is the primary medical therapy for patients with functioning PETs. Over 85% of PETs express receptors for somatostatin,15 and in-vitro studies have shown that secretion of VIP can be inhibited by somatostatin.16 Soga and Yakuwa reported that somatostatin controlled symptoms and normalized VIP levels in 78% of their patients.4 Improvement of symptoms and halting of tumor progression with somatostatin has been noted in some patients who have metastatic disease.4,14,17 Because long-term administration of somatostatin lacks significant side effects, it can be considered for patients who are not good surgical candidates and as a palliative therapy for patients with recurrent disease.
Chemotherapy has been used for patients with metastatic PETs. Most regimens include some combination of interferon, streptozocin, and 5-fluorouracil. Up to half of patients placed on chemotherapy show improvement in their symptoms, regression in tumor size, and increased survival.5 Combining chemotherapy with somatostatin may also have a synergistic effect.5,18
Liver transplants have been documented in patients with PETs that are metastatic to the liver. Florman and colleagues reported 11 patients who underwent orthotopic liver transplantation due to metastatic PETs.8 The 5-year survival rate was 36%. Radio?frequency ablation and chemoembolization of hepatic metastases have been tried with some success.19,20
VIPomas are rare neuroendocrine tumors. They typically present with a constellation of chronic signs and symptoms. This case illustrates that VIPomas sometimes have an acute presentation.
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