treated without surgery. These data provide compelling evidence that patients with sporadic gastrinoma

benefit from surgical exploration and complete tumor resection.

The management of gastrinoma in MEN-1 is not as clear. The surgical treatment of hypercalcemia

caused by parathyroid hyperplasia should precede any surgery for hypergastrinemia in patients with

MEN-1. In these patients, gastrin-secreting tumors are often multicentric and associated with lymph

node metastases. Although some groups have favored exploration only when MEN-1 gastrinoma tumors

exceed 3 cm, it seems that earlier intervention may be warranted.125,126 Unfortunately, more data from

an appropriate clinical trial are needed to better define the timing of surgery for MEN-1 gastrinoma.

In the 1950s and 1960s, most gastrinomas were diagnosed late in the course of the disease, when the

tumor burden was already significant. At that time, effective medical therapy did not exist, nor did

sophisticated radiographic localization and staging techniques. Patients often suffered multiple ulcer

complications, required total gastrectomy to control the ulcer diathesis, and typically succumbed to

continued tumor growth following gastrectomy. Recent reviews of patients with surgically treated

gastrinoma provide room for optimism.127–130 Currently, up to 35% of patients who undergo resection

with curative intent have been rendered eugastrinemic at follow-up. Cure rates approach 60% to 70%

when the extent of disease allows a complete resection.

Most patients with incurable metastatic disease eventually die of tumor growth and dissemination.

Multiple modalities have been used to treat such patients. Chemotherapy including streptozocin, 5-

fluorouracil, and doxorubicin provides response rates of less than 50%.131 Hormonal therapy with

octreotide may relieve symptoms, reduce hypergastrinemia, and diminish hyperchlorhydria.132,133 In

patients with hepatic metastases, aggressive resection for debulking,134–137 hepatic transplantation,138

hepatic artery embolization, and interferon therapy have all been used, with variable results.

VIPOMA (VERNER–MORRISON SYNDROME)

Synonyms for VIPoma include WDHA syndrome (watery diarrhea, hypokalemia, and either achlorhydria

or acidosis) and pancreatic cholera syndrome (Table 56-8). Verner and Morrison139 characterized this

secretory diarrheal syndrome in a 1958 report. Patients characteristically present with intermittent,

severe, watery diarrhea averaging up to 5 L/d. Hypokalemia results from fecal loss of large amounts of

potassium. Low serum potassium levels lead to lethargy, muscle weakness, and nausea. A metabolic

acidosis may be present, due to loss of bicarbonate in the diarrhea. Half of the patients may have

hyperglycemia or hypercalcemia, and cutaneous flushing can be observed in a minority. The diagnosis

of VIPoma is made after other common causes of diarrhea have been excluded (Table 56-9)140 and an

elevated serum VIP level is documented.

Table 56-8 VIPoma

Table 56-9 Differential Diagnosis of Verner–Morrison Syndrome

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Figure 56-9. Several computed tomographic images from a patient with a primary vasoactive intestinal polypeptide-oma (VIPoma)

in the tail of the pancreas. The tumor is nearly spherical. Its location is posterior to the stomach and adjacent to the spleen.

VIP secretion can be episodic, so repeated fasting levels should be measured if there is a strong

clinical suspicion. Preoperative tumor localization is critical, because 10% of patients may have

extrapancreatic tumors located in the retroperitoneum or chest. Most tumors are located in the distal

pancreas where they are amenable to resection via distal pancreatectomy (Fig. 56-9). In most cases,

hepatic metastases accompany the primary tumor. Therapies directed at debulking these metastases

such as resection or ablative strategies are appropriate.

Surgical excision is appropriate in nearly all patients with Verner–Morrison syndrome. Prior to

surgery, fluid and electrolyte imbalances must be corrected. Octreotide can serve as a treatment

adjunct, reducing the levels of circulating VIP, with a resultant decrease in the volume of diarrhea.

Octreotide is also useful for symptom control in the setting of unresectable disease. Chemotherapy

specific for this disease has not been well studied.

GLUCAGONOMA

10 The most common findings in the glucagonoma syndrome are severe dermatitis, mild diabetes,

stomatitis, anemia, and weight loss (Table 56-10). The dermatitis manifests as a characteristic skin rash

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termed necrolytic migratory erythema. This rash exhibits cyclic migrations, and it has been theorized that

the hypoaminoacidemia accompanying glucagonoma is the cause.

Table 56-10 Glucagonoma

The diagnosis of glucagonoma is suggested by the clinical presentation and biopsy of the skin lesions

but is secured by the documentation of high fasting levels of serum glucagon. Most glucagonomas are

located in the body and tail of the gland. These tumors are typically large and bulky, and surgical

resection requires distal pancreatectomy (Fig. 56-10). Metastases are found in most patients and safe

debulking of these should be considered.141 As in patients with VIPoma and insulinoma, octreotide can

be useful in controlling the signs and symptoms (hyperglycemia and dermatitis) associated with

incurable glucagonoma.

SOMATOSTATINOMA

The somatostatinoma syndrome is the least common of the five generally accepted functional pancreatic

endocrine neoplasia syndromes, occurring in less than 1 in 40 million people. The clinical features are

nonspecific including steatorrhea, diabetes, hypochlorhydria, and cholelithiasis (Table 56-11). Fasting

plasma somatostatin levels of greater than 100 pg/mL can be used to confirm the diagnosis.

Most somatostatinomas are located in the pancreatic head or periampullary region.142 Tumors are of

variable size and are often easily localized. Metastatic disease may be present at the time of diagnosis.

Safe resection of the primary tumor (often via pancreaticoduodenectomy) and careful debulking of

hepatic metastases are indicated.

Figure 56-10. Computed tomography with oral and intravenous contrast in a patient with a glucagonoma. The large tumor

appears to be posterior to the stomach and to the right of the aorta from the viewer’s perspective.

Table 56-11 Somatostatinoma

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NONFUNCTIONAL PANCREATIC ENDOCRINE NEOPLASMS

Currently, the majority of patients with neoplasms of the endocrine pancreas have no defined clinical

syndrome and no elevated functional hormone levels. Pancreatic PP and chromogranin A levels may be

elevated, though neither is associated with a clinical syndrome. A study by Mutch et al.143 determined a

relationship between fasting plasma PP levels in patients with MEN-1 and the presence of

radiographically detectable pancreatic endocrine tumor. A PP level that is more than three times the

age-specific normal value is 95% sensitive and 88% specific for a PEN that can be imaged. The majority

of patients with nonfunctional endocrine tumors are asymptomatic, however, those who present with

symptoms will typically complain of abdominal pain, weight loss, or jaundice, caused by the spaceoccupying nature of the mass in the pancreas. Overall, nonfunctional tumors tend to grow more slowly

and have a more indolent course than the highly lethal pancreatic ductal adenocarcinoma, yet the 5-year

survival rate for PENs after resection remains only 65%, with a 10-year survival of 45%.10

Patients with operable disease should undergo formal surgical resection for potential cure via

pancreaticoduodenectomy or distal pancreatectomy, depending on tumor location. Tumor enucleation,

without formal resection may be appropriate for patients with small tumors (<2 cm), significant

medical comorbidities, or those documented to have a low proliferative index (Ki-67). Patients with

locally advanced disease involving the mesenteric vasculature may be candidates for radical mesenteric

vascular resection (Fig. 56-11). With successful treatment, these patients can expect to enjoy a median

survival in excess of 5 years.144,145

METASTATIC PANCREATIC ENDOCRINE TUMORS

At least one-third of patients with malignant PENs present with synchronous liver metastases at the time

of diagnosis.146 A subset of these patients remain asymptomatic and experience prolonged survival even

without aggressive therapy.104 However, overall 5-year survival with liver metastases is less than

50%.147 PENs are one of the few tumors for which a survival advantage for surgical debulking has been

shown.135,146,148–150 In those selected patients where safe surgical resection of greater than 90% of the

tumor burden can be achieved, 5-year survival rates of 60% to 75% have been reported.

Those with unresectable disease to the liver may be candidates for a variety of hepatic directed

therapies for locoregional control and symptom palliation. These include hepatic artery embolization,

radiofrequency/microwave ablation, and infusional chemotherapy.151 Metastatic PENs have shown

partial responses to chemotherapy. In 1992, the results of a trial conducted by the Eastern Cooperative

Oncology Group (ECOG) were published.104 In this study, 105 patients with advanced nonfunctional

endocrine tumors were randomly assigned to one of three groups. The lowest response rate (30%) was

seen in patients receiving chlorozotocin alone, an intermediate response rate (45%) was seen in patients

receiving the combination of streptozotocin plus 5-fluorouracil, and the highest response rate (69%) was

noted in patients receiving streptozotocin plus doxorubicin. The last regimen also showed significant

survival advantage in comparison with the other two treatments. More recent attempts to replicate

these results have been disappointing.152

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Figure 56-11. Computed tomography of a patient with a large PEN(*) replacing the pancreatic body and tail(*), with splenic vein

occlusion, perigastric varices (blue line), and tumor thrombus (red line) growing into the portal vein. This patient underwent a distal

pancreatectomy, splenectomy, and partial portal vein resection with tumor thrombectomy, with complete surgical extirpation of

the malignancy.

Somatostatin analogs are another approach to treating metastatic PENs. Results are more favorable in

tumors that have high-affinity receptors (gastrinomas, VIPomas, glucagonomas, and some nonfunctional

tumors) as compared to insulinomas. Symptomatic improvement occurs in 60% to 90% of patients.

However, an objective tumor response is seen in only 5% to 15% of patients, with stabilization of

disease in 50% or more of patients.153–155 In patients who fail to respond to traditional somatostatin

analogs, such as octreotide and lanreotide, the novel multireceptor-targeted somatostatin analog

pasireotide has shown the ability to offer symptom reduction, primarily because of its ability to bind to

four of the five known somatostatin receptor subtypes.156

Two new targeted therapies have been approved for use in the setting of advanced metastatic PENs

based upon the results of large multicenter phase 3 clinical trials. The first is the agent sunitinib malate

(Sutent, Pfizer Inc.), an oral, small molecule, multitargeted tyrosine kinase inhibitor initially approved

for the treatment of advanced renal cell carcinoma and refractory gastrointestinal stromal tumors. It has

activity against VEGF and PDGF. In a large (171 patients) multinational, randomized, double-blind,

placebo-controlled phase 3 trial in patients with advanced, well-differentiated PENs, patients receiving

sunitinib had a median progression-free survival of 11.4 months compared with 5.5 months in the

placebo group (p < 0.001).157 The second agent everolimus, an oral inhibitor of the mammalian target

of rapamycin (mTOR) was also tested in a large (410 patients) international, randomized, double blind,

placebo-controlled phase 3 trial (RADIANT-3), in patients with advanced low- and intermediate-grade

PEN. The median progression free survival of patients in the everolimus arm was 11 months compared

to 4.6 months in the placebo arm (p < 0.001). Both of these oral agents have a favorable side-effect

profile, and further studies to delineate their role in the treatment of PENs are currently underway.158

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