Carcinoids of the Gastrointestinal Tract – Common Signs and Symptoms, Diagnosis and Treatment

Carcinoid tumors are uncommon cancers. Although they can develop in other organs, especially the lung, they generally arise in the intestinal tract, including the stomach, pancreas, small bowel, appendix, and rectum. They are the most common tumors of the appendix, occurring in 1 out of every 300 appendectomies. They make up 30 percent of small bowel tumors but less than 2 percent of all gastrointestinal malignancies.

In their early stages, carcinoid tumors are highly treatable and often curable. They are usually slow growing, and the risk of metastasis is related to the size of the primary tumor. Because these tumors are indolent in their behavior and the patient is usually asymptomatic early in the disease, the tumor often goes undetected for many years. Consequently, the disease is often in a more advanced stage at the time of diagnosis.

Small bowel carcinoids may occur in multiple sites (about 25 percent of patients have multiple tumors) and, except for those of rectal origin, may produce biologically active hormones and peptides. In many cases, there are no symptoms, so some carcinoid tumors are discovered incidentally during abdominal operations performed for other reasons. The survival of most people with carcinoid tumors is quite good, although symptoms may develop when the tumor cannot be removed, when it recurs after treatment, or when there is metastatic disease.

Manifestations of the carcinoid syndrome

Types There are no meaningful cell type (histologic) variations that help predict the clinical course of these tumors. Carcinoids are broadly defined as neuroendocrine or APUD (amine precursor uptake and decarboxylation) tumors. They are classified as foregut, midgut, or hindgut, according to site of primary tumor. Foregut tumors include lung, gastric, duodenal, and pancreatic tumors; midgut tumors include those in the small bowel, appendix, and the first portion of the large intestine; and hindgut tumors are from the remainder of the large intestine and the rectum. Each classification of carcinoid tumors represents not only differences in location of the primary tumor, but also where the tumor is likely to spread and differences in hormone production. Malignant midgut carcinoids may produce at least two hormones, serotonin and substance P, but some carcinoid tumors are nonfunctional and do not release any substances.

How It Spreads Carcinoid tumors spread by direct invasion of the underlying layers of tissue (submucosally). They can also spread via lymphatics to regional lymph nodes and through the bloodstream to the liver, lung(s), bones, or other organs.

The site of origin and size of the primary tumor are important in determining whether the carcinoid tumor is likely to spread. A tumor less than 1/2 inch (1 cm) rarely metastasizes. But 88 percent of patients with tumors larger than 3/4 inch (2 cm) have metastases, and 18 percent of these develop the carcinoid syndrome (see “Common Signs and Symptoms,” below).

What Causes It Unknown

Risk Factors

Factors that put an individual at risk have not been identified. It is exceedingly rare for carcinoids to be hereditary. However, there are certain genetic mutations found to be associated with the development of the disease. The majority of mutations associated with carcinoid tumors appear to be spontaneous mutations rather than a result of an inherent risk.

Screening

There are no effective screening methods.

Common Signs and Symptoms

Symptoms are unusual in the early stages. The tumors are small and grow slowly and the symptoms so vague, any changes noticed are considered normal. When pronounced symptoms do occur, the tumor has already spread in 90 percent of patients. The most common symptoms associated with gastrointestinal tumors are periodic abdominal pain, intermittent intestinal obstruction, and kinking of the bowel. Gastrointestinal bleeding is uncommon and ulcerations of the tumor are rare.

In addition to the symptoms caused by the tumor, there may be symptoms of the carcinoid syndrome. This is characterized by facial flushing, wheezing, diarrhea, and cardiac valvular disease. Midgut carcinoid tumors are more likely to be associated with the syndrome compared to foregut tumors. Hindgut tumors are usually asymptomatic. The syndrome is associated with abnormal amounts of the two hormones produced by malignant carcinoids, serotonin and substance P. The syndrome occurs in approximately 10 percent of patients with carcinoid tumors, almost always because of carcinoid metastases in the liver.

Diagnosis

Physical Examination

• Palpating the abdomen to identify an abdominal mass and/or an enlarged liver.

• Examination of the facial skin to identify prominent skin veins (telangiectasis) and flushing.

• Listening with a stethoscope for signs that may be associated with carcinoid syndrome—heart murmur and wheezing on expiration.

Blood and Other Tests

• Chromogranin A (CgA) is a general biochemical marker for neuroendocrine tumors. Not all carcinoid tumors overproduce and secrete measurable CgA, but most do. If levels are abnormal, it provides a marker for the disease.

• Metastatic carcinoid tumors may be diagnosed by the twenty-four-hour urine 5-hydroxyindoleacetic acid (5-HIAA) test, which detects elevated levels of 5-HIAA, a metabolic product of the serotonin produced by the tumor. Plasma serotonin levels represent only the level at the time of blood sampling, but the 5-HIAA urine sample provides a twenty-four-hour picture of the serotonin levels, thus providing a more accurate measure for abnormal serotonin production. False positive 5-HIAA tests can be caused by foods such as bananas, avocados, and pineapple and by certain drugs. The laboratory should provide a complete list of foods to be avoided during urine collection.

Imaging

• X-rays of the chest and gastrointestinal tract (small bowel and barium enema).

• Endoscopic evaluation of the stomach may include endoscopic ultrasound (EUS), bronchoscopy for lung tumors, enteroclysis (small bowel enema) for tumors of the small intestine, and colonoscopy to detect large intestinal or rectal tumors.

• CT or MRI scans (with contrast) of the abdomen to detect primary tumors and liver metastases.

• Octreoscan is a nuclear medicine test to determine where the tumor has spread. This test uses a radio-labeled somatostatin analogue that binds to receptors in a lock-and-key fashion. These receptors are located on the tumor cell surface and allow the tumor to be detected through imaging by a nuclear medicine camera. This imaging is used for initial staging of disease and restaging when disease progression is suspected. Since this test reveals somatostatin receptors, it also provides a means for evaluation if the tumor cells would be responsive to somatostatin analogue therapy.

Biopsy Tissue biopsy is the most definitive means of diagnosing the disease. Biopsies may be done of the primary tumor and/or the metastatic lesions.

Staging

There are no specific staging criteria for carcinoids. The tumors are usually referred to as local, local/regional, or metastatic, with emphasis on the extent and location of metastatic disease.

Treatment Overview

Surgery is the standard therapy. The extent of disease spread is important in deciding treatment options.

Surgery Surgical removal of the tumor is the standard treatment for cure. If the primary tumor is localized and can be removed, the five-year survival rate is in the range of 70 to 90 percent. Since carcinoid tumors are usually slow growing, even patients with tumors that can’t be removed have an average survival of several years. Surgery often offers excellent relief from symptoms—for example, by removing the liver metastases causing the carcinoid syndrome or by resecting or bypassing intestinal obstructions. Such surgery may add years to a patient’s life, an uncommon result of surgery for other types of liver metastases.

Radiation Radiation therapy may be used for symptomatic treatment of bone metastases.

Chemotherapy There has been modest success with chemotherapy. Drug combinations of 5-fluorouracil and streptozocin (Zanosar) have had responses of 10 to 30 percent. Clinical trials evaluating newer drugs are preferable.

Palliation Drugs such as Periactin (cyproheptadine), alpha- and beta adrenergic blockers, chlorpromazine (Thorazine), and corticosteroids may be used to alleviate the symptoms related to the carcinoid syndrome.

Octreotide (Sandostatin), a somatostatin analogue, is very effective in decreasing the secretion of serotonin and can help relieve symptoms of the carcinoid syndrome such as flushing, diarrhea, and wheezing. Interferon-alpha may alleviate symptoms and arrest tumor growth.

Treatment of Localized Tumors by Site

Appendiceal Carcinoids

Appendiceal tumors account for 22 percent of all carcinoids. They are treated by appendectomy and, in fact, are usually diagnosed for the first time at surgery. Lesions less than 3/4 inch (2 cm) in diameter are essentially 100 percent curable.

Appendiceal tumors larger than 3/4inch (2 cm) are rare and treated like a carcinoma of the colon. For these larger tumors, removal of the right side of the colon and the lymphatics is recommended.

Five-Year Survival 99 to 100 percent

Rectal Carcinoids

These account for a quarter of all carcinoids. Rectal carcinoids less than 1/2 inch (1 cm) can be treated adequately by local excision (fulguration), with cure rates approaching 100 percent.

Carcinoid lesions larger than 3/4 inch (2 cm) are treated surgically. As with carcinoma, an abdominal-perineal resection may be necessary, but sphincter-preserving surgery may be performed in some cases.

Lesions between 1/2 and 3/4 inch (1 to 2 cm) are in a “gray zone” and receive individualized treatment depending on age, operative risk, and acceptability of a colostomy. The cure rate is excellent.

Five-Year Survival 76 to 83 percent

Small Bowel Carcinoids

Small bowel tumors make up 28 percent of all carcinoids. Conservative local excision is sufficient for tumors less than 1/2 inch (1 cm) in diameter. For larger tumors, a wedge of the tissues supporting the bowel (mesentery) containing the regional lymph nodes should also be removed.

Anyone with a tumor larger than 3/4 inch (2 cm) should be followed closely for a minimum of ten years. The follow-up program should include quarterly or semiannual CT scan of the abdomen and measurements of CgA and urinary 5-HIAA levels.

Five-Year Survival 54 to 67 percent

Treatment of Invasive and Metastatic Carcinoids

Regional Gastrointestinal Carcinoids

Carcinoid tumors with regional metastasis or local extension should be treated by aggressive surgery. If all visible malignant disease can be removed, long-term survival rates will be excellent.

No surgical adjuvant treatment is known to be helpful.

If the regional disease cannot be removed, palliative surgery—to remove all the accessible disease, for example—should be carried out.

Chemotherapy is not required; these patients frequently have many months or even years of comfortable life without further treatment.

Metastatic Carcinoid Tumors

A number of standard treatment options are available for metastatic carcinoid tumors.

Surgery This has considerable value when there are large liver metastases involving surgically accessible areas of the liver. Liver metastases that recur after surgery should be considered for another resection if they are in an area where the operation can be done with minimal complications. Since these tumors are often slow growing, such surgery may result in significant improvement in life span.

• Radiofrequency ablation of liver metastasis is an option for multiple smaller tumors (less than 2?3/4 inches [7 cm]) and it is often used in conjunction with surgical removal of larger liver tumors. A needle is placed in the tumor, and radiofrequency current is transmitted. This current heats the tumor tissue, causing tumor cell death. The heat also closes up small blood vessels, thereby minimizing the risk of bleeding.

• For very carefully selected patients with slowly progressive disease and symptomatic carcinoid heart disease, heart valve replacement may be indicated.

Hepatic Artery Embolization This is an option for bulky or symptomatic liver metastases that are not surgically resectable. Hepatic artery embolization is used to reduce the blood flow through the hepatic artery, the artery that feeds most liver cancer cells. A material that can plug up the artery is injected. Most of the healthy liver cells will be unaffected because they get their blood supply from the portal vein. A catheter is inserted into an artery in the groin area and threaded up into the liver. A dye is usually injected into the bloodstream at this time to allow the doctor to see the path of the catheter by a special type of X-ray called angiography. Once the catheter is in place and it is confirmed that the portal vein is not blocked, small particles are injected into the artery, cutting off the blood supply to the tumor cells.

Embolization may be done with or without chemotherapy. This can lead to substantial tumor regression. It can also cause significant side effects—abdominal pain, fever, nausea, and a short-term worsening of the syndrome—but many patients do experience substantial relief from symptoms.

Embolizations are often performed over several procedures until the desired effect is appreciated, usually one month apart. This procedure can be repeated years later in the course of disease management.

Radiation The role of radiation therapy in managing carcinoid tumors with distant metastasis is restricted to relief of symptoms, most commonly from bone involvement. However, localized metastasis will occasionally respond to radiation therapy.

Supportive Therapy There are a number of ways to manage symptoms from metastatic disease with medication:

• Diarrhea, if not severe, will frequently respond to standard antidiarrheal medications such as Lomotil, Imodium, or tincture of opium and to dietary changes such as restricting consumption of foods high in fat.

• The somatostatin analogue octreotide (Sandostatin) has been shown to be useful in improving symptoms of the carcinoid syndrome and may be life saving in carcinoid crisis (sudden exacerbation of symptoms). It targets the cell receptors that control the abnormal production and release of the hormones that cause the syndrome and carcinoid heart disease. This method of therapy is the standard for reducing elevated levels of 5-HIAA.

• Interferon-alpha preparations may have a role in controlling symptoms of the carcinoid syndrome and/or in arresting tumor growth.

• Acute symptoms—carcinoid crisis—may be prevented by pretreatment, and an active crisis can be reversed with short-acting octreotide. Some specific drugs are to be avoided in these patients because of the risk of causing the release of vasoactive substances. This is especially true during surgery and in the treatment of low blood pressure.

Chemotherapy Although activity with a variety of single agents and drug combinations has been reported—5-fluorouracil (5-FU), doxorubicin (Adriamycin), and dacarbazine (DTIC) or 5-FU + streptozocin—response rates seldom exceed 30 percent. Complete responses are uncommon, and the duration of the response may be short, if chemotherapy is used alone.

Chemotherapy should be used for palliation in patients with symptoms and in the case of liver metastases, after blocking the hepatic (liver) artery and then giving chemotherapy (chemoembolization).

Investigational A novel approach has been introduced recently where octreotide is tagged with a radionuclide that kills tumor cells. This is given intravenously and targets tumor cells with somatostatin receptors. Newer drugs that target other molecular pathways are also being investigated.

Treatment Follow-Up

Patients should be evaluated every three to twelve months. The evaluation should include

• physical examination;

• twenty-four-hour urine 5-HIAA levels;

• chromogranin A;

• octreoscan, if required;

• chest X-ray, if required; and

• abdominal MRI or CT scan, if required. If a CT scan is used, it is preferable to use a three-phase scan.

Recurrent Cancer

The selection of further treatment depends on many factors, including the therapy initially used, the site of the recurrence, and individual considerations.

Since some tumors grow rather slowly, attempts to remove them again or multiple operations to remove liver metastases are worthy of consideration. Reducing tumor volume may provide long-term relief of symptoms.

Investigational treatments are appropriate and should be considered when standard treatment fails.

The Most Important Questions You Can Ask

• How are carcinoids different from the usual cancers of the bowel?

• What tests are needed to follow my progress after surgery?

• What does a rising urine 5-HIAA mean?

• What are the toxic side effects of chemotherapy?

• What is the role of repeated surgeries for recurrent carcinoid cancers?

• Am I eligible for any research or investigational protocols?