Paraneoplastic syndromes

Definition

Paraneoplastic syndromes (PS) are rare disorders triggered by the immune system's response to cancer cells, or by remote effects of tumor-derived factors. These syndromes are believed to occur when cancer-fighting anti-bodies or white blood cells, known as T-cells, mistakenly attack normal body cells. These disorders typically affect middle-aged to older people and are most common in patients with lung, ovarian, lymphatic, or breast cancer.

Description

Paraneoplastic syndromes are defined as clinical syndromes involving non-cancerous effects in the body that accompany malignant disease, and can affect any part of the nervous system from the cerebral cortex to peripheral nerves and muscles. In a broad sense, these syndromes are collections of symptoms that result from substances produced by the tumor, occurring far away from the tumor itself. When a tumor arises, the body may produce antibodies to fight it, by binding to and helping in the destruction of tumor cells. Unfortunately, in some cases, these antibodies cross-react with normal tissues and destroy them, which may stimulate the onset of PS. However, not all PS are associated with such antibodies.

Neurological symptoms generally develop over a period of days to weeks, and usually occur prior to the discovery of cancer, which can complicate diagnosis. In these cases, additional information should raise the possibility that the patient may have a hidden cancer and that neurological symptoms could be paraneoplastic. Symptoms include fatigue , weakness, muscular pain in upper arms, difficulty walking, burning, numbness or tingling sensations in the limbs (peripheral paresthesia), dry mouth, sexual function difficulty, and drooping eyelids.

Neurological signs may include dementia with or without brain stem signs, rapid and irregular eye movements, and ophthalmoplegia (weakness or paralysis in muscles that move the eye). Paraneoplastic syndromes involving the nervous system include: Lambert-Eaton myasthenic syndrome (LEMS), stiff person syndrome (SPS), encephalomyelitis (inflammation of the brain and spinal cord), myasthenia gravis (MG), cerebellar degeneration (CD), limbic and/or brain stem encephalitis, neuromyotonia, opsoclonus myoclonus (OM), and sensory neuropathy.

Demographics

Most paraneoplastic syndromes are rare, affecting less than 1% of persons with cancer. Exceptions include LEMS, which affects about 3% of patients with small-cell lung cancer; MG, which affects about 15% of persons with thymoma; and demyelinating peripheral neuropathy , which affects about 50% of patients with the rare osteosclerotic form of plasmacytoma. No race, age, or sex preference has been reported.

Causes and symptoms

Most or all paraneoplastic syndromes are activated by the body's immune system. In response to a tumor, the immune system produces an antigen that is normally expressed exclusively in the nervous system. The tumor antigen is identical to the normal antigen, but for unknown reasons the immune system identifies it as foreign and mounts an immune response.

In general (although not always), PS develops in an acute or subacute fashion, over days or weeks. Symptoms may include difficulty in walking and/or swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech, memory loss, vision problems, sleep disturbances, dementia, seizures , sensory loss in the limbs, and vertigo. The nervous system disability is usually severe.

Diagnosis

Currently, paraneoplastic syndromes are diagnosed using two different technologies in testing blood. Blood testing with western blot using recombinant human antigens is a highly specific method; it can clearly distinguish between different paraneoplastic antibodies. Immunohistochemistry can detect paraneoplastic antibodies in blood serum, providing a general diagnosis, but cannot distinguish between the different PS antibodies.

The physician should search for cancer using the most sensitive technology available, including magnetic resonance imaging (MRI) and a fluorodeoxyglucose body positron emission tomography (PET) scan.

Treatment team

Due to the many manifestations of paraneoplastic syndromes, PS should be evaluated clinically by a coordinated team of doctors, including medical oncologists, surgeons, radiation oncologists, endocrinologists, hematologists, neurologists, and dermatologists.

Treatment

Because PS are considered to be immune-mediated disorders, two treatment approaches have been used: removal of the source of the antigen by treatment of the underlying tumor, and suppression of the immune response. For many PS, the first approach is the only effective treatment. In the LEMS and MG, plasma exchange or intravenous immune globulin is usually effective in suppressing the immune response.

Physicians often also prescribe a combination of either plasma exchange or intravenous immune globulin and immunosuppressive agents such as corticosteroids, cyclophosphamide, or tacrolimus. For most paraneoplastic syndromes, immunotherapy is not effective.

Recovery and rehabilitation

Some disorders such as the LEMS and MG respond well to immunosuppressant drugs and to treatment of the underlying tumor. The peripheral neuropathy associated with osteosclerotic myeloma generally resolves when the tumor is treated with radiotherapy. A few disorders may respond to treatment of the underlying tumor, immuno-suppression, or both, or they may resolve spontaneously. In many instances, it is not clear whether the PS resolve spontaneously or in response to treatment. Disorders involving the central nervous system , such as encephalomyelitis associated with cancer or paraneoplastic cerebellar degeneration, usually respond poorly to treatment, although they may stabilize when the underlying tumor is treated.

Clinical trials

As of mid-2004, the numerous clinical trials recruiting participants for the study and treatment of paraneo-plastic syndromes include:

• Interferon and Octreotide to Treat Zollinger-Ellison Syndrome and Advanced Non-B Islet Cell Cancer
• Evaluating Pancreatic Tumors in Patients with Zollinger-Ellison Syndrome
• Treatment of Zollinger-Ellison Syndrome
• The Use of Oral Omeprazole and Intravenous Pantoprazole in Patients with Hypersecretion of Gastric Acid

Updates information on these and other ongoing trials can be found at the National Institutes of Health web-site for clinical trials at <http://www.clinicaltrials.gov>.

Prognosis

The prognosis for persons with paraneoplastic syndromes depends on the specific type of PS, and the progression of the underlying cancer. LEMS and MG are neuromuscular junction diseases, which can recover function once the causal insult is removed, because there is no neuronal loss. Disorders such as CD are usually associated with neuronal damage, and because they evolve subacutely and treatment is often delayed, neurons die, making recovery much more difficult. Some central nervous system disorders such as OM may not involve cellular loss and, thus, patients with these disorders, like those with LEMS, have the potential for recovery.

Special concerns

It is important that caregivers for those with paraneo-plastic syndromes receive adequate support. The disorder typically emerges suddenly and without warning. The neurological manifestations of PS are complex and often require 24-hour patient care. Many caregivers will require quick access to information on caring for a disabled person. This includes information on social security benefits, insurance coverage, handicapped license plates, evaluations for physical therapy; medical equipment such as hospital beds, ultra-light wheelchairs, handheld showerheads, and home healthcare and visiting nurses; and social workers and other support services.

Resources

BOOKS

Ruter, U., et al. Paraneoplastic Syndromes. Basel: S. Karger Publishing, 1998.

PERIODICALS

Robert, B. D., and P. B. Jerome. "Paraneoplastic Syndromes Involving the Nervous System." New England Journal of Medicine 349 (2003): 1543–1554.

Sutton, I., and J. B. Winer. "The Immunopathogenesis of Paraneoplastic Neurological Syndromes." Clinical Science 102 (2002): 475–486.

OTHER

"NINDS Paraneoplastic Syndromes Information Page." National Institute of Neurological Disorders and Stroke. May 1, 2004 (June 2, 2004). <http://www.ninds.nih.gov/health_and_medical/disorders/paraneoplastic.htm>.

Santacroce, Luigi. "Paraneoplastic Syndromes." eMedicine. May 1, 2004 (June 2, 2004). <http://www.emedicine.com/med/topic1747.htm>.

ORGANIZATIONS

American Autoimmune Related Diseases Association. 22100 Gratiot Avenue, Eastpointe, MI 48201-2227. (586) 776-3900 or (800) 598-4668; Fax: (586) 776-3903. [email protected]. <http://www.aarda.org>.

National Cancer Institute (NCI)—National Institutes of Health. Bldg. 31, Rm. 10A31, Bethesda, MD 20892-2580. (301) 435-3848. [email protected]. <http://cancernet.nci.nih.gov>.

American Cancer Society. 1599 Clifton Road, NE, Atlanta, GA 30329-4251 or (800) ACS-2345 (227-2345). <http://www.cancer.org>.

Francisco de Paula Careta

Iuri Drumond Louro, MD, PhD