Glucagonoma

Definition

Endocrine pancreatic cancer is a disease in which cancerous cells originate within the tissues of the pancreas that produce hormones.

Description

The pancreas is a six- to eight-inch long, slipper-shaped gland located in the abdomen. It lies behind the stomach, within a loop formed by the small intestine. Other nearby organs include the gallbladder, spleen, and liver. The pancreas has a wide end (head), a narrow end (tail), and a middle section (body). A healthy pancreas is important for normal food digestion and plays a critical role in the body's metabolic processes. The pancreas has two main functions, each performed by distinct types of tissue. The exocrine tissue secretes fluids into the other organs of the digestive system, while the endocrine tissue secretes substances that are circulated in the bloodstream. The exocrine pancreas makes up the vast majority of the gland; it produces pancreatic juices containing enzymes that help break down proteins and fatty food. The endocrine tissue of the pancreas makes up only 2% of the gland's total mass. It consists of small patches of cells that produce hormones (like insulin) that control how the body stores and uses nutrients. These patches are called islets (islands) of Langerhans or islet cells and are interspersed evenly throughout the pancreas. Each islet contains approximately 1,000 endocrine cells and a dense network of capillaries (tiny blood vessels), which allows immediate entry of hormones into the circulatory system.

Pancreatic tumors are classified as either exocrine or endocrine tumors depending on which type of tissue they arise from within the gland. Endocrine tumors of the pancreas are very rare, accounting for only 5% of all pancreatic cancers. The majority of endocrine pancreatic tumors are functional adenocarcinomas that overproduce a specific hormone. There are several types of islet cells and each produces its own hormone or peptide (small protein molecule). Functional endocrine tumors are named after the hormone they secrete. Insulinoma is the most common tumor of the endocrine pancreas. Patients with this disease usually develop hypoglycemia due to increased insulin production that leads to abnormally low blood sugar levels. Gastrinoma, a disease in which gastrin (hormone which stimulates stomach acid production) is overproduced, causes multiple ulcers in the upper gastrointestinal (GI) tract. Gastrinoma was first described in patients with a rare form of severe peptic ulcer disease known as Zollinger-Ellison syndrome (ZES). The less common glucagonoma causes mild diabetes due to excess glucagon (hormone which stimulates glucose production) secretion. Other rare islet cell tumors include vipoma (vasoactive intestinal peptide) and somatostatinoma. Nonfunctional pancreatic endocrine tumors are not associated with an excess production of any hormone and can be difficult to distinguish from exocrine pancreatic cancer. Cancers of the endocrine pancreas are relatively slow-growing compared to the more common ductal adenocarcinomas of the exocrine pancreas.

Demographics

Between one and four cases of insulinoma occur per million people per year, and 90% of these tumors are benign. They occur mostly between the ages of 50 and 60 and affect men and women equally. Less than three cases of gastrinoma per million people are diagnosed each year, but it is the most common functional islet cell tumor in patients with multiple endocrine tumors, a condition known as multiple endocrine neoplasia (MEN) syndrome. Vipoma and glucagonoma are even rarer and they occur more frequently in women. Somatostatinoma is exceedingly uncommon, and less than 100 cases have been reported worldwide. Nonfunctional islet cell cancers account for approximately one-third of all cancers of the endocrine pancreas, and the majority of these are malignant.

Causes and symptoms

There are no known causes of islet cell cancer, but a small percentage of cases occur due to hereditary syndromes such as MEN. This is a condition that frequently causes more than one tumor in several endocrine glands, such as the parathyroid and pituitary, in addition to the islet cells of the pancreas. Twenty-five percent of gastrinomas and less than 10% of insulinomas occur in MEN patients. Von Hippel-Lindau (VHL) syndrome is another genetic disorder that causes multiple tumors, and 10% to 15% of VHL patients will develop islet cell cancer.

Symptoms vary among the different islet cell cancer types. Insulinoma causes repeated episodes of hypoglycemia, sweating, and tremors, while patients with gastrinoma have inflammation of the esophagus, epigastric pain, multiple ulcers, and possibly diarrhea. Symptoms of glucagonoma include a distinctive skin rash, inflammation of the stomach, glucose intolerance, weight loss, weakness, and anemia (less common). Patients with vipoma have episodes of profuse, watery diarrhea, even after fasting. Somatostatinoma causes mild diabetes, diarrhea/steatorrhea (fatty stools), weight loss, and gallbladder disease. Nonfunctional endocrine tumors frequently produce the same symptoms as cancer of the exocrine pancreas such as abdominal pain, jaundice, and weight loss.

Diagnosis

A thorough physical exam is usually performed when a patient visits a doctor with the above symptoms; however, functional endocrine tumors of the pancreas tend to be small and are not detected by palpating the abdomen. Once other illnesses such as infection are ruled out, the doctor will order a series of blood and urine tests. The functional endocrine tumors can be identified through increased levels of hormone in the bloodstream.

Functional endocrine tumors can occur in multiple sites in the pancreas and are often small (less than 1 cm), making them difficult to diagnose. Nonfunctional tumors tend to be larger, which makes them difficult to distinguish from tumors of the exocrine pancreas. Methods such as computed tomography (CT) scan and magnetic resonance imaging (MRI) are used to take pictures of the internal organs and allow the doctor to determine whether a tumor is present. Somatostatin receptor scintigraphy (trade name OctreoScan) is an imaging system used to localize endocrine tumors, especially gastrinomas and somatostatinomas. Endoscopic ultrasound (EUS) is a more sensitive technique that may be used if a CT scan fails to detect a tumor. Endocrine tumors usually have many blood vessels, so angiography may be useful in the doctor's assessment and staging of the tumor. Surgical exploration is sometimes necessary in order to locate very small tumors that occur in multiple sites. These techniques also help the doctor evaluate how far the tumor has spread. A biopsy can be taken to confirm diagnosis, but more often, doctors look at the size and local invasion of the tumor in order to plan a treatment strategy.

Treatment team

Patients with islet cell cancer are cared for by a number of specialists from different disciplines. Medical oncologists, gastroenterologists, radiologists, and surgeons all interact with the patient to develop an appropriate treatment plan. Endocrinologists play an important role in helping patients with diabetes maintain steady blood sugar levels. Much of the treatment of islet cell cancer focuses on relieving symptoms of the tumor through medication that inhibits hormone overproduction. It is best for patients to work with doctors who are experienced in treating this rare form of cancer.

Clinical staging, treatments, and prognosis

Staging

The staging system for islet cell cancer is still evolving, but the tumors typically fall into three categories: cancers that arise in one location within the pancreas, cancers that arise in several locations within the pancreas, and cancers that have spread to nearby lymph nodes or to other organs in the body.

Treatments

Surgery is the only curative method for islet cell cancers, and studies have shown that an aggressive surgical approach can improve survival and alleviate symptoms of the disease. As with most forms of cancer, the earlier it is diagnosed, the greater the chance for survival. With the exception of insulinoma, the majority of islet cell tumors are malignant at the time of diagnosis, and more than half are metastatic. However, surgery and chemotherapy have been shown to improve the outcome of patients even if they have metastatic disease. Surgery may include partial or total removal of the pancreas, and in patients with gastrinoma, the stomach may be removed as well. Streptozocin, doxorubicin, and 5-fluorouracil (5-FU, or fluorouracil) are chemotherapeutic agents commonly used in the treatment of islet cell cancer. Patients may experience nausea and vomiting as well as kidney toxicity from streptozocin, and bone marrow suppression from doxorubicin. Hormone therapy is used to relieve the symptoms of functional tumors by inhibiting excess hormone production. Other techniques may be used to block blood flow to the liver in an attempt to kill the cancer cells that have spread there. Abdominal pain, nausea, vomiting and fever may result from this type of treatment. Radiation has little if any role in the treatment of islet cell cancer.

Prognosis

Islet cell cancers overall have a more favorable prognosis than cancers of the exocrine pancreas, and the median survival from diagnosis is three and half years. This is mainly due to their slow-growing nature. Insulinomas have a five-year survival rate of 80% and gastrinomas have 65%. When malignant, islet cell cancers do not generally respond well to chemotherapy, and the treatment is mainly palliative. Most patients with metastasis do not survive five years. Islet cell cancer tends to spread to the surrounding lymph nodes, stomach, small intestine, and liver.

Coping with cancer treatment

Patients should discuss with their doctors any side effects they experience from treatment. Many drugs are available to relieve nausea and vomiting associated with cancer treatments and for combating fatigue. Insulin may be prescribed if patients develop diabetes as a result of partial or total removal of their pancreas. Special diets or fluids may be recommended if patients have more than one digestive organ removed. These patients may require intravenous feeding after surgery until they recover.

Clinical trials

Because this is such a rare disease, relatively few clinical trials are available to people with islet cell cancer. Most are investigating the efficacy of new chemotherapeutic drugs or combinations of drugs and biological therapies. R115777 is an agent being tested in combination with trastuzumab (Herceptin) for patients with advanced or metastatic adenocarcinoma. Two new drugs that are antineoplastons, A10 and AS2-1, are being examined together as a treatment regimen for patients with metastatic or incurable neuroendocrine tumors. Patients should ask their doctors whether they qualify for these or other clinical trials.

Prevention

There are no known risk factors associated with sporadic islet cell cancer. Therefore, it is not clear how to prevent its occurrence. Individuals with MEN syndrome or VHL, however, have a genetic predisposition to developing islet cell cancer should be screened regularly in an effort to catch the disease early.

Special concerns

Many patients find it helpful to join support groups after being diagnosed with cancer. Discussing the condition with others who are experiencing a similar situation may help to relieve anxiety and depression, which are often associated with cancer and its treatment. Medication may also be prescribed to alleviate depression. Patients should learn as much as they can about their illness and find out what their treatment options are. It is important for patients to remember that each cancer has unique characteristics and responds differently to treatment depending on those characteristics.

KEY TERMS

Adenocarcinoma

A malignant tumor that arises within the tissues of a gland and retains its glandular structure.

Angiography

Diagnostic technique used to study blood vessels in a tumor.

Biopsy

Removal and microscopic examination of cells to determine whether they are cancerous.

Chemotherapy

Drug treatment administered to kill cancerous cells.

Endocrine

Refers to glands that secrete hormones circulated in the bloodstream.

Endoscopic Ultrasonography (EUS)

Diagnostic imaging technique where an ultrasound probe is inserted down a patient's throat to determine if a tumor is present.

Gastrinoma

Tumor that arises from the gastrin-producing cells in the pancreas.

Insulinoma

Tumor that arises from the insulin-producing cells in the pancreas.

Islets of Langerhans

Clusters of cells in pancreas that make up the endocrine tissue.

QUESTIONS TO ASK THE DOCTOR
• What type of islet cell cancer do I have?

• Do you have experience in treating this form of cancer?

• Is my tumor benign or malignant?

• What is my prognosis?

• Can my tumor be removed by surgery?

• What medication will I need to take?

• Am I at risk for developing other endocrine tumors?

• Is there a clinical trial I can participate in?

• Is there a support group available?