WDHA Syndrome Treatment & Management

  • Author: Sandeep Mukherjee, MB, BCh, MPH, FRCPC; Chief Editor: Julian Katz, MD   more...
 
Updated: May 11, 2012
 

Approach Considerations

A multispecialty team composed of gastroenterologists, surgeons, radiologists, and oncologists should evaluate patients with WDHA syndrome.

Because of the rarity of VIPomas, most treatment recommendations are based on experience with pancreatic endocrine tumors. Most experts agree, however, that chemotherapy and interferon are indicated for patients with extensive metastatic disease. Even so, no agreement exists as to when such treatment should be started.

Management of WDHA syndrome is initially directed at treating symptoms related to hormone excess and, subsequently, at the tumor itself.

Resuscitation

Rehydration and correction of electrolyte and acid-base abnormalities are the most urgent steps in patient care. These can be lifesaving measures because the most common cause of death in these patients is acute renal failure associated with hypokalemia.

Octreotide

This is a long-acting, synthetic analog of somatostatin, which inhibits the release of VIP. Octreotide controls diarrhea in as many as 87% of patients and may reduce the tumor size in a minority of patients. Slow-release lanreotide and Sandostatin LAR are 2 longer-acting preparations that have been developed. Lanreotide is not available in the United States.

Antidiarrheals

Antidiarrheal medications, such as loperamide (Imodium), may be used in addition to octreotide in patients with breakthrough diarrhea.

Surgery

Surgical resection currently remains the cornerstone of successful treatment and provides the only hope for cure, because 50-60% of VIPomas are malignant. Therefore, all patients should be considered for exploratory laparotomy, with the exception of those with unresectable metastatic disease or with coexisting medical illnesses that preclude surgery.[43]

No surgical discussion is complete without reference to the role of liver transplantation in metastatic WDHA syndrome. Although this was first described in 1990, caution should be exercised when evaluating patients with extrahepatic pancreatic endocrine tumors, particularly noncarcinoid tumors.

Referrals

Patients should be advised to seek treatment at a major referral center that has expertise in this field. This is true particularly for the subset of patients with nonresectable disease who may be candidates for innovative, potentially lifesaving treatment protocols.

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Chemotherapy

Several chemotherapeutic agents have been used to treat patients with metastatic disease. Streptozotocin and doxorubicin have emerged as the agents of choice. This is based primarily on a 1992 Eastern Cooperative Oncology Group (ECOG) study in which the combined use of these agents was associated with a 69% response rate, which was significantly higher than the 45% rate for the streptozotocin and 5-fluorouracil (5-FU) combination or the 30% response rate with chlorozotocin alone.

A review of 322 patients with metastatic disease treated with interferon alfa suggested that interferon has minimal tumoricidal activity, although it may stabilize tumor growth in 20-30% of patients.

A case report from France demonstrated major clinical improvement and regression in tumor size in a patient with jejunal VIPoma metastatic to the liver and peritoneum who was treated with a combination of interferon alfa and 5-FU.

Because of the rarity of WDHA syndrome and the incomplete understanding of its natural history, interpreting the effectiveness of chemotherapeutic interventions is difficult.

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Hepatic Artery Occlusion

Because most metastatic tumors in the liver are highly vascular and receive their blood supply through the hepatic artery, hepatic artery occlusion, with or without chemotherapy, may be used for palliative treatment in patients with a patent portal vein.

In one large study involving 111 patients with metastatic pancreatic endocrine tumors or carcinoid tumors, hepatic artery occlusion was associated with an objective beneficial response in 60% of patients. This rate increased to 80% of patients with the use of chemotherapy (ie, doxorubicin, dacarbazine, streptozotocin, 5-FU). In this study, chemoembolization was also associated with longer remission time (ie, 4 mo vs 18 mo).

Another study reported that chemoembolization with doxorubicin in iodized acid combined with gelatin or sponge particles resulted in improved symptoms in 68-100% of patients and a decrease in tumor size and/or hormone levels in 57-100% of patients.

A report by Case et al reported dramatic improvement in diarrhea following hepatic artery embolization in a patient with VIPoma and liver metastases who had not responded to surgical debulking, antidiarrheals, octreotide, and targeted radioisotope injections.[6]

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Surgical Exploration

During exploration, the liver should be examined carefully for metastatic disease and an attempt should be made to resect isolated hepatic metastasis.

A careful examination of the entire pancreas requires an extended Kocher maneuver, with incision of the retroperitoneum on the superior and inferior aspects of the pancreatic body. Mobilization of the spleen may be required in order to examine the pancreatic tail, and the small bowel should be explored for extrapancreatic tumors.

Although VIPomas are usually intrapancreatic, nearly 10% tumors may have an ectopic location, occurring frequently along the ganglia of the autonomic nervous system. Intraoperative ultrasonography is recommended for identifying tumors that were not detected preoperatively and for establishing the presence of local invasion.

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Pancreatectomy

Isolated tumors in the pancreatic body or tail should be removed by distal pancreatectomy, with or without splenectomy. Laparoscopic resection has been performed successfully in 2 patients, but experience remains limited.

More proximal tumors in the pancreatic head or body may be treated with enucleation rather than a Whipple procedure because these more radical techniques have not always been associated with better outcomes.

However, a review of 125 patients with neuroendocrine tumors by the Johns Hopkins Group revealed that the most common operation performed was pancreaticoduodenectomy (in 40% of patients). The most favorable outcome in this retrospective series was observed in patients with benign functional tumors and in those with completely resected malignant tumors.

Blind distal pancreatectomy

Blind distal pancreatectomy is a controversial procedure that is occasionally performed in symptomatic patients in whom no tumor is found, because of the 20% rate of islet cell hyperplasia in symptomatic patients.

Because other hormones may cause the diarrheagenic syndrome, one reasonable alternative when faced with this clinical conundrum is to close the abdomen and to perform further localizing studies.

Vaccination

Pneumococcal vaccination should be administered to all patients who undergo distal pancreatectomy and splenectomy.

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Cytoreductive/Debulking Surgery

Although only a minority of patients with metastatic WDHA syndrome have resectable disease, whether patients whose illness is well controlled with medical therapy experience any long-term benefit from debulking surgery is unclear.

Indeed, while cytoreductive/debulking surgery may prolong life expectancy in certain patients, the natural history of metastatic WDHA syndrome is not well understood because of its rarity. As a result, no studies have evaluated cytoreductive surgery in a controlled, prospective manner to determine if survival is improved.

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Contributor Information and Disclosures
Author

Sandeep Mukherjee, MB, BCh, MPH, FRCPC  Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center

Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

Coauthor(s)

Randall E Brand, MD  Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center

Randall E Brand, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Pancreatic Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Richard K Gilroy, MBBS, FRACP  Associate Professor, Medical Director of Liver Transplantation and Hepatology, Department of Internal Medicine, Kansas University Medical Center

Disclosure: genetech, gilead, NPS pharmaceuticals Salary Speaking and teaching

Chief Editor

Julian Katz, MD  Clinical Professor of Medicine, Drexel University College of Medicine

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

Additional Contributors

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Manoop S Bhutani, MD Professor, Co-Director, Center for Endoscopic Research, Training and Innovation (CERTAIN), Director, Center for Endoscopic Ultrasound, Department of Medicine, Division of Gastroenterology, University of Texas Medical Branch; Director, Endoscopic Research and Development, The University of Texas MD Anderson Cancer Center

Manoop S Bhutani, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Institute of Ultrasound in Medicine, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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