VIPoma

A VIPoma is a rare neuroendocrine tumor arising primarily in the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas that releases large amounts of vasoactive intestinal polypeptide (VIP). This process leads to chronic watery diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea with concomitant hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia and dehydration, as well as wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing and flushing (known as Verner-Morrison or WDHA (chronic Watery Diarrhea, Hypokalemia, Achlorhydria) syndrome). Most tumors arise sporadically, but some are associated with MEN 1. Diagnosis is established by measuring serum VIP levels. Treatment consists of medical management of symptoms and complete surgical removal of the tumor when possible.

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Overview

Definition

A VIPoma is a rare neuroendocrine tumor that secretes vasoactive intestinal polypeptide (VIP).

Epidemiology

  • Incidence: 1 in 1,000,000 people per year
  • 95% arise in the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas, and 75% of symptomatic cases arise in the tail of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas.
  • 3rd most common pancreatic neuroendocrine tumor (after insulinoma and gastrinoma Gastrinoma A gastrinoma is a tumor that secretes excessive levels of the hormone gastrin and is responsible for Zollinger-Ellison syndrome (ZES). Gastrinomas are frequently associated with multiple endocrine neoplasia 1 (MEN 1) and can arise from the pancreas, stomach, duodenum, jejunum, and/or even from the lymph nodes. Gastrinoma)
  • Age of onset: 30–50 in adults and 2–4 in children

Etiology

  • Arise from neuroendocrine cells, most commonly islet cells in pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas
  • Most are isolated and sporadic, but 5% are associated with MEN 1.

Pathophysiology and Clinical Presentation

Anatomy

  • 95% arise within the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas, and 75% within the tail of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas.
  • Usually solitary and > 3 cm
  • Other locations common in children:
    • Adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands
    • Sympathetic ganglia
  • Less common locations:
    • Lung
    • Colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix/ rectum Rectum The rectum and anal canal are the most terminal parts of the lower GI tract/large intestine that form a functional unit and control defecation. Fecal continence is maintained by several important anatomic structures including rectal folds, anal valves, the sling-like puborectalis muscle, and internal and external anal sphincters. Rectum and Anal Canal
    • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
Anatomy of the pancreas

Anatomy of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas

Image: “Blausen 0699 PancreasAnatomy2” by Blausen. License: CC BY 3.0

VIPoma syndrome

  • Also known as Verner-Morrison syndrome or WDHA syndrome:
    • Chronic Watery Diarrhea
    • Hypokalemia (causes muscle cramps, weakness, and arrhythmias)
    • Achlorhydria
  • Caused by excessive unregulated secretion of VIP:
    • VIP binds to receptors on intestinal epithelial cells.
    • Activation of cellular adenylate cyclase and cAMP production result in fluid and electrolyte secretion into lumen.
    • Other effects:
      • Vasodilation
      • Inhibition of gastric acid secretion
      • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones resorption
      • Enhanced glycogenolysis

Clinical presentation

  • Watery diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea:
    • Usually intermittent
    • Not affected by fasting
    • Tea-colored stools (> 700 mL/day, up to 5 L)
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain is mild or minimal.
  • Flushing episodes (in 20% of patients)
  • Symptoms related to hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia and dehydration:
    • Lethargy
    • Nausea/vomiting
    • Muscle weakness/cramps

Diagnosis

History

  • Unexplained high-volume diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea (often intermittent)
  • Flushing episodes
  • Family or personal history of MEN 1

Laboratory studies

  • Elevated serum VIP > 75 pg/mL (should be confirmed with repeat testing)
  • Abnormal electrolyte levels:
    • Hypokalemia
    • Metabolic alkalosis Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. Metabolic Alkalosis
    • Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia: can be intermittent and correspond to diarrheal episodes
    • Hyperglycemia
    • Hypochlorhydria
    • Iron and B12 deficiency

Imaging

  • CT scan with contrast: Sensitivity approaches 100%.
  • MRI: more sensitive than CT for detecting liver metastases
  • Somatostatin receptor scintigraphy: whole-body scan using radioactively labeled octreotide
  • Endoscopic ultrasound (EUS): rarely used
  • PET scan: good for localization and staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis
Ct scan showing large necrotic pancreatic vipoma

Computed tomography scan showing large necrotic pancreatic VIPoma

Image: “Multi-visceral resection of pancreatic VIPoma in a patient with sinistral portal hypertension Portal hypertension Portal hypertension is increased pressure in the portal venous system. This increased pressure can lead to splanchnic vasodilation, collateral blood flow through portosystemic anastomoses, and increased hydrostatic pressure. There are a number of etiologies, including cirrhosis, right-sided congestive heart failure, schistosomiasis, portal vein thrombosis, hepatitis, and Budd-Chiari syndrome. Portal Hypertension” by Joyce DL, Hong K, Fishman EK, Wisell J, Pawlik TM. License: CC BY 2.0

Management

Primary mass

  • Medical:
    • Repletion of fluid and electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes
    • Somatostatin analogs (octreotide, lanreotide)
      • Bind to somatostatin receptors
      • Inhibit serotonin release
    • 2nd-line treatments for diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea refractory to somatostatin analogs:
      • Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
      • Clonidine
      • Loperamide
  • Surgical: distal pancreatectomy for primary tumors

Metastatic disease

  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver resection
  • Hepatic artery embolization
  • Ablations (radiofrequency and cryoablation)
  • Drugs:
    • Somatostatin analogs
    • Streptozocin
    • Sunitinib
    • Everolimus

Prognosis

  • 60%–80% are metastatic at diagnosis.
  • Prognosis depends on grade, stage, and surgical resectability.
  • Median survival of VIPoma patients is 96 months.

Differential Diagnosis

  • Infectious diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea: diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea caused by a variety of bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview and viruses (e.g., Vibrio Vibrio Vibrio is a genus of comma-shaped, gram-negative bacilli. It is halophilic, acid labile, and commonly isolated on thiosulfate-citrate-bile-sucrose (TCBS) agar. There are 3 clinically relevant species: Vibrio cholerae (V. cholerae), Vibrio vulnificus (V. vulnificus), and Vibrio parahaemolyticus (V. parahaemolyticus). Vibrio cholerae, Escherichia coli). Usually acute onset and frequently self-limited. Diagnosis established by history and stool cultures. Treatment entails supportive management and antibiotics in certain cases.
  • Malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion: malfunction of intestinal wall that results in insufficient absorption of breakdown products. May present as diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, steatorrhea, abdominal distention, flatulence, weight loss, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, vitamin deficiencies, and/or failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive. Diagnosis established by a combination of stool studies, blood work, and sometimes endoscopy and imaging. Treatment is usually supportive.
  • Carcinoid syndrome Carcinoid syndrome Carcinoid tumors are small, well-differentiated, slow-growing neuroendocrine tumors (NET). Carcinoid syndrome describes the signs and symptoms associated with unregulated vasoactive hormone production by neuroendocrine tumors. Carcinoid tumors are most commonly found in the GI and bronchopulmonary tracts. Carcinoid Tumors and Syndrome: constellation of symptoms associated with production of serotonin and other substances by carcinoid tumors. Usually presents with diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, flushing, and wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing. Diagnosis established by measurement of serotonin metabolites and imaging to confirm presence of tumor. Treatment includes surgical resection and symptomatic management.
  • Gastrinoma: gastrin-secreting tumor that causes Zollinger-Ellison syndrome. Arises from pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas, stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach, duodenum, jejunum, and/or even lymph nodes. Symptoms include refractory peptic ulcers and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea. Diagnosis established by fasting gastrin levels. Treatment includes surgical resection and symptomatic management.

References

  1. Bergsland E. (2020). VIPoma: Clinical manifestations, diagnosis, and management. Retrieved January 27, 2021, from https://www.uptodate.com/contents/vipoma-clinical-manifestations-diagnosis-and-management
  2. Cameron J.L. (2004). Current Surgical Therapy. 8th Edition. 
  3. Grier J.F. (1995). WDHA (watery diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia, achlorhydria) syndrome: clinical features, diagnosis, and treatment. Southern Medical Journal. 88(1), 22–24. https://doi.org/10.1097/00007611-199501000-00002
  4. Smith S.L., et al. (1998). Vasoactive intestinal polypeptide secreting islet cell tumors: a 15-year experience and review of the literature. Surgery. 124(6), 1050–1055. https://doi.org/10.1067/msy.1998.92005

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