Paraneoplastic syndromes are rare disorders caused by substances that are secreted by a benign tumor, a malignant (cancerous) tumor, or a malignant tumor's metastases. The disturbances caused by paraneoplastic syndromes occur in body organs at sites that are distant or remote from the primary or metastatic tumors. Body systems that may be affected by paraneoplastic syndromes include neurological, endocrine, cutaneous, renal, hematologic, gastrointestinal, and other systems. The most common manifestations of paraneoplastic syndromes are cutaneous, neurologic, and endocrine disorders. An example of a cutaneous paraneoplastic disorder are telangiectasias, which can be caused by breast cancer and lymphomas. Eaton-Lambert syndrome is a neurologic paraneoplastic syndrome that can be caused by a variety of tumors including small cell lung cancer, lymphoma, breast, colon and other cancers. Syndrome of inappropriate antidiuretic hormone (SIADH) is an endocrine paraneoplastic syndrome, which is seen in as many as 40% of patients diagnosed with small cell lung cancer.
Approximately 15% of patients already have a paraneoplastic disorder at the time of initial diagnosis with cancer. As many as 50% of all cancer patients will develop a paraneoplastic syndrome at some time during the course of their disease. Some clinicians categorize the anorexia, cachexia, and fever which occur as a result of cancer as metabolic paraneoplastic syndromes. Virtually all patients diagnosed with cancer are affected by at least one of these metabolic paraneoplastic syndromes.
Paraneoplastic syndromes can occur with any type of malignancy. However, they occur most frequently with lung cancer, specifically small-cell lung carcinoma. Other types of cancer that commonly cause paraneoplastic syndromes are breast cancer and stomach cancer. With the exception of Wilms' tumor and neuroblastoma, paraneoplastic syndromes do not usually occur in children diagnosed with cancer.
In general, paraneoplastic syndromes may be present in the patient before a diagnosis of cancer is made, or, as stated earlier, may be present at the time the patient is first diagnosed with cancer. Most paraneoplastic syndromes appear in the later stages of the disease. Frequently, the presence of a paraneoplastic syndrome is associated with a poor prognosis. Paraneoplastic syndromes are difficult to diagnose and are often misdiagnosed. Some paraneoplastic syndromes may be confused with metatastic disease or spread of the cancer. The presence of the syndrome may be the only indication that a patient has a malignancy or that a malignancy has recurred. Paraneoplastic syndromes may be useful as clinical indicators to evaluate the response of the primary cancer to the treatment. Resolution of the paraneoplastic syndrome can be correlated with tumor response to treatment. That is, if the paraneoplastic syndrome resolves, the tumor has usually responded to the treatment.
Causes
Paraneoplastic syndromes occur when the primary or original tumor secretes substances such as hormones, proteins, growth factors, cytokines, and antibodies. The substances are referred to as mediators. These mediators have effects at remote or distant body organs, which are termed target organs. Mediators interfere with communication between cells in the body. This miscommunication results in abnormal or increased activity of the cell's normal function. For example, a lung tumor may cause the paraneoplastic syndrome, ectopic Cushing's syndrome, which is the result of abnormal functioning of the pituitary gland located in the brain. In this example, the lung cancer is the primary tumor and the pituitary gland is the target organ. Ectopic Cushing's Syndrome is caused by overproduction of the mediator, adrenocorticotropic hormone (ACTH).
Treatment
There are usually two approaches taken in the treatment of paraneoplastic syndromes. The first step is treatment of the cancer that is causing the syndrome. This treatment can be surgery, administration of chemotherapy, biotherapy, radiation therapy, or a combination of these therapies. The next approach is to suppress the substance or mediator causing the paraneoplastic syndrome. Often treatment targeted to the underlying cancer and to
the paraneoplastic syndrome occur at the same time. However, even with treatment, irreversible damage to the target organ can occur.
Selected Paraneoplastic Syndromes
SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE (SIADH).
SIADH is a common paraneoplastic syndrome that affects the endocrine system. This syndrome is most often associated with small-cell lung cancer; however, other cancers such as brain tumors, leukemia, lymphoma, colon, prostate, and head and neck cancers can lead to SIADH. SIADH is caused by the inappropriate production and secretion of argininevasopressin or antidiuretic hormone (ADH) by tumor cells. Patients with SIADH may not have symptoms, especially in the early stages. When symptoms do occur they are usually related to hyponatremia, which leads to central nervous system toxicity if left untreated. Signs and symptoms associated with hyponatremia include fatigue, anorexia, headache and mild alteration in mental status in early stages. If SIADH remains untreated, symptoms can progress to confusion, delirium, seizures, coma, and death. Treatment approaches for SIADH are to treat the underlying tumor and restriction of fluids. More severe cases may require the administration of medications.
EATON-LAMBERT SYNDROME (ELS).
ELS has been associated with a number of cancers including small cell lung cancer, lymphoma, breast, stomach, colon, and prostate cancers. Potential mediators associated with paraneoplastic ELS are antibodies that interfere with release of acetylcholine at the neuromuscular junction. This interference prevents the flow of calcium, which results in decreased or absent impulse transmission to muscle. The disruption in muscular impulse transmission leads to mild symptoms including weakness in the legs and thighs, muscle aches, muscle stiffness, and muscle fatigue. Treatment of ELS includes administration of corticosteroids, intravenous immunoglobulin, and plasma-pheresis. Depending on the extent of damage, irreversible loss of function may occur even with treatment.
ECTOPIC CUSHING'S SYNDROME.
Cushing's Syndrome is most often associated with small-cell lung cancer, ovarian cancer, and medullary cancers of the thyroid. ACTH precursors are activated by tumor cells that results in overproduction of ACTH by the pituitary gland. Signs and symptoms of ectopic Cushing's Syndrome include hypertension, hyperglycemia, hypokalemia, edema, muscle weakness, and weight loss. The primary approach to treating ectopic Cushing's Syndrome is to treat the underlying cancer. In early stages, surgery is the treatment of choice. However, surgery is not usually an option for patients diagnosed with small-cell
cancer of the lung. If the tumor is unable to be removed or controlled, or if the patient has severe symptoms, then treatment targeted to the syndrome is initiated. Medical therapy is usually focused on inhibiting cortisol production and involves the use of medications such as ketoconazole and aminoglutethimide.
Resources
BOOKS
Block, J. B. "Paraneoplastic Syndromes" In Cancer Treatment, edited by J. S. Berek. Philadelphia: Saunders, 1995, pp. 245-264.
John, W. J., K. A. Foon, and R. A. Patchell. "Paraneoplastic Syndromes" In Cancer: Principles and Practice, edited by V. T. DeVita, S. Hellman, and S. A. Rosenberg. Philadelphia: Lippincott-Raven, 1997, pp. 2, 397-2, 422.
Midthun, D. E., and J. R. Jett. "Clinical Presentation of Lung Cancer" In Lung Cancer: Principles and Practice, edited by H. I. Pass, J. B. Mitchell, D. H. Johnson, and A. T. Tau ris. Philadelphia: Lippincott-Raven, 1996, pp. 421-435.
PERIODICALS
Nathensen, L. and T. C. Hall. "Introduction: Paraneoplastic Syndrome." Seminars in Oncology (1997): 265-268.
Zumsteg, M. M. and D. S. Casperson. "Paraneoplastic Syn dromes in Metastatic Disease." Seminars in Oncology Nursing (1998): 220-229.
"10 Most Commonly Asked Questions about Paraneoplastic Syndromes." Williams and Wilkins 1998. 3 April 2001. 27 June 2001. <http://www.wwilkins.com/theneurologist/articles/paraneoplastic.html>.
Melinda Granger Oberleitner, RN, DNS
Anorexia
—Loss of appetite.
Cachexia
—Severe malnutrition, emaciation, muscle wasting and debility associated with the inability to absorb the nutritional value of food eaten.
Cutaneous disorders
—Disorders affecting the skin.
Hypokalemia
—Decreased levels of the electrolyte potassium in the blood.
Hyponatremia
—Decreased levels of the electrolyte sodium in the blood.
Metastasis
—Tumors which originate from the primary or original tumor at distant locations in the body; secondary tumors.
