Islet Cell Carcinoma (Endocrine Pancreas)

Introduction

Pancreatic islet cells are part of the diffuse neuroendocrine system of the gut and pancreatic endocrine system. Islet cells commonly are referred to as APUD cells, a name derived from their high amine content and capacity for amine precursor uptake with decarboxylation. Tumors of pancreatic islet cells are uncommon. They may manifest as sporadic tumors or as part of certain syndromes, including multiple endocrine neoplasia type 1(MEN 1) and von Hippel–Lindau (VHL) disease. Islet cell tumors may be functional or nonfunctional; although nonfunctional islet cell tumors are not uncommon at autopsy, most islet cell tumors with clinical manifestations are functional.

Functioning tumors produce a clinical syndrome as a result of excessive hormone production. Clinical features of the syndrome depend on tumor cell type. Pancreatic islet cell tumors may secrete 2 or more polypeptide hormones. Functioning tumors usually are small at presentation, and localizing these tumors can be challenging to the radiologist. Hormonal and biochemical parameters are invaluable for skillful interpretation of the imaging and clinical features and to arrive at a specific diagnosis. Nonfunctioning tumors usually are larger and present because of their size or metastatic spread.

Prognosis for patients with MEN 1 is usually poor. Islet cell tumors in this group are often multiple and malignant. In patients with MEN 1 and Zollinger-Ellison (ZE) syndrome, surgical cure is usually not possible. However, surgical cure can be achieved in patients with MEN type-I and insulinomas, although recurrences are frequent. Imaging is used to localize primary and metastatic lesions and to determine resectability or alternative palliative and curative treatment options. This article reviews the role of imaging in the management of islet cell tumors.

Pathophysiology

Tumors arising from APUD cells are termed APUDomas. Pearse initially suggested that APUD cells were derived from neural crest cells, although researchers now generally recognize that gastroenteropancreatic APUD cells (including pancreatic islets) probably arise from endoderm. APUD cells contain the enzyme neuron-specific enolase, which is the universal marker for hyperplasia and neoplasia of such cells. Pancreatic islet cell tumors are capable of secreting more than one type of hormone, and as a response to excessive production of a particular hormone, regulatory hypersecretion of other hormones may occur.

Approximately 15-25% of patients with pancreatic APUDomas have MEN 1. Good correlation exists between the type of islet cell tumor and the type of hormone produced in excess, although little correlation appears between tumor size, hormone production, and severity of clinical symptoms.

Immunohistochemical staining generally does not allow differentiation between benign and malignant tumors. Recent studies of CD44s have shown some promising results. Endocrine pancreatic tumors express CD44s and isoforms differentially. Imam and coworkers (2000) have shown that expressions of 2 isoforms of CD44s (v6 and v9) seem to be related more to the benign form of the tumor and may serve as a predictor of good prognosis. A recent report on the role of telomerase activity in pancreatic endocrine tumors may be useful to distinguish benign from malignant tumors. The presence of telomerase activation in the tumor predicts malignancy in islet cell tumors.

Frequency United States

Persons with islet cell carcinomas have a better prognosis than those with pancreatic exocrine adenocarcinomas and account for less than 2% of cases of pancreatic cancer in the United States.

International

Sporadic islet cell tumors are more common than islet cell tumors as a part of MEN 1. Worldwide prevalence of these tumors is approximately 1 in 100,000.

Mortality/Morbidity

Prognosis is variable for islet cell tumors, and treatment options vary for different types of tumors, including surgical resection, debulking of the primary lesion, chemotherapy, and/or radiotherapy for malignant tumors. Benign islet cell tumors should be surgically resected to abolish the hormone-induced effects of the tumor. Currently, the recommended strategy for pancreatic endocrine tumors is complete resection of liver metastasis in patients with limited disease who are good operative candidates. Nonsurgical techniques that are used to treat hepatic metastasis include lipiodol-transcatheter arterial embolization, cryotherapy, and radiofrequency ablation.

In many patients with islet cell tumors, metastases progress slowly. Therefore, there may be a role for "watchful waiting" in some patients with nonsecreting liver metastasis. Researchers believe that most patients with malignant neoplasm live for a long time and often die of causes unrelated to the tumor. Prolonged survival is common with extensive pancreatic islet cell disease, although some patients deteriorate rapidly and die in less than a year. Clinically silent larger tumors have a worse prognosis than smaller tumors and are associated with a survival rate of approximately 60%.

Sex

Except for gastrinoma, almost all tumors have a slightly higher incidence in females than in males. No significant sex predilection exists.

Age

Islet cell tumors occur in young to middle-aged patients. Some tumors have been reported at both extremes of age, including newborns.

Presentation

Almost all sporadic islet cell tumors are symptomatic because of their excessive biologically active hormone production. Most tumors produce an excess of a single type of hormone. The average time from onset of symptoms to diagnosis of the tumor is 2.7 years.

Insulinoma

• Insulinoma is the most common and well-known islet cell tumor of the pancreas, accounting for more than 75-80% of sporadic functioning pancreatic islet cell tumors. Approximately 10% are associated with MEN 1. Typical acute symptoms include sweating, trembling, palpitations, nervousness, and apprehension from catecholamine release in response to hypoglycemia. Symptoms are subtle rather than acute and abrupt in most patients. A wide variety of symptoms can occur, including episodic behavioral disturbances with memory loss. Some symptoms may simulate a psychiatric disorder. Headaches, confusion, visual disturbances, motor weakness, palsy, and ataxia may occur, progressing to unconsciousness and coma.
• In the early stages of the disease, symptoms are likely to occur in the early morning or late afternoon, especially after strenuous exercise or if the patient has been fasting. Long-term hypoglycemia may result in irreversible brain damage with no response to glucose administration.
• The classic clinical sign of insulinoma is the Whipple triad, a starvation period resulting in hypoglycemia (fasting glucose < 50 mg/dL), which is immediately relieved by intravenous (IV) dextrose. The most important finding is the prevalence of high levels of insulin secretion in the presence of concurrent hypoglycemia.
• The rule of nines can be applied to insulinomas in that they are sporadic in 90% of patients, solitary in 90%, benign in 90%, less than 5 cm in 90%, and 95% intrapancreatic. No predilection exists for a specific site within the pancreas.

Gastrinoma

• Gastrin-secreting tumors arise from nonbeta islet cells and are known as gastrinomas. The second most common islet cell tumors, they are sporadic in approximately 70% of patients and are a part of the MEN 1 in approximately 30%. Gastrinomas frequently are malignant and are multiple in 70% of cases. Most of the benign adenomas are multiple. Sporadic gastrinomas are less often malignant. Conversely, 60-70% of gastrinomas associated with MEN 1 are malignant with metastasis at diagnosis.
• Patients who exhibit the triad of peptic ulcer diathesis, marked gastric hypersecretion, and gastrin-producing nonbeta islet cell tumor of pancreas are grouped under the clinical entity ZE syndrome. Approximately 65% of patients are male. Ulcer perforation occurs in approximately 30% of patients with ZE syndrome. Ulceration is most common in the duodenal bulb. Other sites include the second, third, and fourth part of the duodenum, stomach, and jejunum. Solitary ulcer is seen in 90% of cases, and multiple ulcers are observed in only 10%.
• Pathologically, 60% of gastrinomas are malignant islet cell tumors, 30% of gastrinomas are benign adenomas, and 10% of patients with ZE syndrome have islet cell hyperplasia.
• Clinical features include symptoms related to hypergastrinemia, such as abdominal pain, diarrhea, vomiting, hematemesis, melena, and weight loss. Many diagnostic tests are available to confirm the diagnosis. Localization and demonstration of the tumor allows one to make management decisions, especially when considering surgical resection. Many patients can be managed medically with H2 blockers.
• Glucagonomas are uncommon tumors of the islet cells and are derived from alpha cells. Almost all symptomatic glucagonomas are sporadic and nonhereditary. Asymptomatic glucagonoma is rare in patients with MEN 1.
• Glucagonoma may be associated with necrolytic erythema migrans, diarrhea, diabetes, glossitis, weight loss, malabsorption, and anemia. Unexplained thromboembolic complications occur in approximately 25% of patients, most commonly in the form of deep venous thrombosis and pulmonary embolism. The mean size of these tumors is 6.4 cm, ranging from 2.5-25 cm. Approximately 75% of glucagonomas are malignant. The tumor is almost always solitary and is seen predominantly in the body and tail. Ectopic sites have been reported.
• The most common site of metastatic glucagonoma is the liver; the regional peripancreatic lymph nodes are second. Liver metastasis is seen in 50% of patients at the time of diagnosis.

Vipoma

• Vipomas are islet cell tumors derived from the delta cells predominantly in the body and tail. Almost all cases are sporadic and nonfamilial. Few cases have been reported in patients with MEN 1. Two thirds are seen in women.
• A distinct syndrome termed Verner-Morrison syndrome, described by Verner and Morrison in 1958, is associated with this islet cell tumor. The mean age of adults with Verner-Morrison syndrome is 47 years, ranging from 19-67 years.
• The syndrome also is known as watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome, with the predominant feature consisting of copious diarrhea of tea-colored watery stool. Stool volume usually ranges from 6-8 L per day, which mimics cholera (hence the term pancreatic cholera). The diarrhea is related to the liberation of vasoactive intestinal peptide (VIP) by the tumor, which relaxes vascular smooth muscle. VIP also paralyzes the gallbladder, inhibits motor activity of the small bowel, and causes a cutaneous flush by relaxing smooth muscle. Vipomas are commonly malignant, with evidence of metastasis in approximately 50% of adults with the disease; they are benign in approximately 30%.

Somatostatinoma

• Somatostatinomas are tumors derived from D cells that contain somatostatin in the pancreatic islets. Unger (1977) suggested that somatostatin acts physiologically as an inhibitory modulator that regulates the amount and ratio of insulin and glucagon released into systemic circulation.
• The syndrome causes diarrhea, steatorrhea, weight loss, gastric hyposecretion, and occasionally diarrhea. Commonly found in the body or tail of the pancreas, somatostatinoma can occur anywhere in the gland. Somatostatinomas are often large tumors and measure approximately 3 cm in diameter. Most are malignant with metastases to the liver.

Nonfunctioning islet cell tumor

• Nonfunctioning islet cell tumors are groups of islet cell tumors that probably do elaborate polypeptides but are nonhyperfunctioning. They may be sporadic or part of MEN 1. They constitute approximately 15-25% of all islet cell tumors and are the third most common islet cell tumor after insulinoma and gastrinoma. Patient age, sex, and histologic features and location of the tumors are similar to those of functioning islet cell tumors. They are detected incidentally from their large size, with resultant mass effect and compression of adjacent structures. GI bleeding may develop because of varices, peptic ulceration, or invasion of a mesenteric vessel. They are located predominantly in the pancreatic head.
• Barium studies may reveal mass effect caused by the tumor, with extrinsic impression on bowel or obstruction signs. Nonfunctioning tumors may exhibit tumor vascularity and early venous filling, which does not necessarily indicate malignancy. Malignant transformation occurs in 80-100% of patients. They are easily localized by cross-sectional imaging. Nodular calcifications are seen in 20-25%, with contrast enhancement on CT in 83%.

Multiple endocrine neoplasia type 1

• MEN 1, or Wermer syndrome, is an inherited endocrine disorder, transmitted by mendelian dominance, that is characterized by involvement of multiple endocrine glands elaborating excessive hormones from hyperfunctioning tumors or hyperplastic endocrine cells.
• Tumors in MEN 1 tend to be multiple in the involved organ, and some may be malignant. The most common sites of involvement are the parathyroids, followed by pancreatic islets. The glands involved in MEN 1 are (1) parathyroids, (2) pancreatic islet cells, (3) anterior pituitary, (4) adrenal cortices, and (5) thyroid gland. They also may be associated with carcinoid, lipoma, thymoma, buccal mucosal tumor, colonic polyposis, and Ménétrier disease.
• Clinical symptoms may develop at any time from childhood to old age. Typically, they develop during the third or fourth decade of life. Symptoms depend on the hyperfunctioning state of the tumors. MEN is an all-or-none phenomenon in that the pituitary, the parathyroids, and the pancreas are involved in virtually all affected individuals.
• Symptoms of hyperparathyroidism with laboratory evidence may be seen in almost all patients. Muscle weakness, fatigability, anorexia, constipation, polyuria, and polydipsia are frequent complaints. Increased bone resorption leads to bone pain and nephrocalcinosis.
• Clinical manifestations of pancreatic islet cell abnormalities frequently do not arise until 5-10 years after the patient exhibits evidence of hyperparathyroidism. Gastrinomas are the most frequent tumors arising in these patients, followed by insulinomas.

Preferred Examination

No universally agreed-upon algorithm exists in the radiologic investigation of islet cell tumors of the pancreas. The diagnosis usually is made by the clinician, and the role of the radiologist is to localize, demonstrate the extent, and stage the lesion, thereby allowing correct management. The best modality for diagnosis is debatable and depends on the expertise of the radiologist at each institution. Larger lesions are easily identifiable by modern cross-sectional imaging techniques. Smaller lesions are difficult to demonstrate, requiring more sophisticated imaging and meticulous technique.

Endoscopic ultrasonography (EUS) is performed by using a 10-MHz transducer incorporated into an endoscope. Lesions are seen as well-rounded, oval echogenic, or hypoechoic areas in the gland parenchyma. A retrospective study by Boukhman et al (1999) evaluated the sensitivities of different techniques to localize insulinomas as follows:

• Arteriography - 47%
• CT - 24%
• Preoperative ultrasound (US) - 50%
• MRI - 30%
• Gadolinium-enhanced MRI - 40%
• Transhepatic venous sampling - 55%
• Intraoperative palpation - 76%
• Intraoperative ultrasonography - 91%

EUS is superior to single-slice spiral CT and should replace the latter for preoperative detection of pancreatic insulinomas. However, because EUS is an invasive study, it should be reserved for patients in whom noninvasive modalities fail to localize the expected tumor. However, multislice CT with 1-mm collimation may prove to be an effective imaging modality. A prospective trial comparing EUS with multislice CT is needed

Pancreas, Adenocarcinoma

Other Problems to Be Considered

When the clinical diagnosis has been established by biochemical and hormonal assays, no radiologic differential diagnosis exists for functioning islet cell tumors. When a hypervascular mass is detected in the pancreas without clinical symptomatology of an endocrine tumor, other pancreatic masses in the differential diagnosis include the following:

• Pancreatic adenocarcinomas are commonly associated with jaundice and, on imaging, demonstrate obstructive ductal enlargement. These features are less common in islet cell tumors. While most islet cell tumors tend to have well-demarcated margins, pancreatic adenocarcinomas often are poorly marginated, infiltrative tumors.
• Hypervascularity is another differentiating feature from other pancreatic tumors, especially adenocarcinoma, which is hypovascular.
• MRI is helpful in characterizing islet cell tumors, which may be markedly hyperintense on T2-weighted and short tau inversion-recovery (STIR) images. They usually demonstrate marked enhancement in the hepatic arterial dominant phase (HAP) after gadolinium administration. Conversely, adenocarcinoma is usually less hyperintense on T2-weighted images and relatively hypovascular as compared with a normal pancreas in the HAP.

Metastatic disease to the pancreas is rare and can occur from the following (all hypervascular):

• Renal cell carcinoma
• Leiomyosarcoma
• Melanoma
• Carcinoid
• Adrenal carcinoma
• Thyroid carcinoma
• Angiosarcoma

Other primary sites include the following:

• Lung cancer
• Breast carcinoma
• Ovarian carcinoma
• Hepatocellular carcinoma

In the Mayo clinic series, the most frequent metastasis to the pancreas was from renal cell carcinoma. This easily can be diagnosed by demonstrating the primary renal tumor but may be more problematic if the tumor was resected and was low grade. Solid and papillary neoplasms are rare, low-grade malignant tumors more commonly seen in women. The mass is most frequently located in the tail of the pancreas with solid and cystic components. They are hypovascular, show minimal enhancement, or may be completely cystic with a mean size of 10 cm. These tumors may contain blood from hemorrhagic necrosis, giving a hyperintense signal on T1-weighted MR images.

• A rare tumor of the pancreas
• Often hypervascular

• Primary or secondary lymphoma may occur in the pancreas.
• It occurs as a large homogeneous hypovascular mass, infrequently with cystic areas.
• Secondary lymphoma demonstrates peripancreatic lymphadenopathy with displacement of the vessels.

• Sarcoma is rare in the pancreas.
• Primary sarcomas occasionally are hypervascular.
• Metastases to the pancreas from sarcomas originating elsewhere can be hypervascular.

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