Paraneoplastic Syndromes Earliest Sign of Some Cancers

MONTREAL—Paraneoplastic syndromes are increasingly being recognized as the earliest warning signs of some cancers, according to presentations at the Presidential Symposium of the 123rd Annual Meeting of the American Neurological Association (ANA).

These syndromes are particularly associated with small-cell lung cancers (SCLC), thymomas, lymphomas, and melanomas. They are caused either by antibodies that are produced against tumor antigens and that also attack neural structures, or by antibodies produced by the tumor itself. Some paraneoplastic syndromes improve only with successful treatment of the tumor, but others respond to modalities such as plasma exchange and corticosteroids.

“Paraneoplastic syndromes are remote effects of cancer that are not a direct result of the tumor mass or its metastases,” said Alan Pestronk, MD, of Washington University School of Medicine. “The syndromes may occur before or after the onset of clinical manifestations of the tumor, sometimes years before or after.”

Paraneoplastic syndromes are particularly common in patients who have lost 15% or more of body weight, Dr. Pestronk said. Nearly all such patients have disorders of muscle or nerve, such as type II muscle fiber atrophy or distal sensory neuropathy. If such a syndrome is present, there is a high probability of finding a neoplasm.

“If you find what appears to be a paraneoplastic syndrome, you need to look for a neoplasm—repeatedly, over time,” he said. He also has found that paraneoplastic syndromes can be more disabling than the associated neoplasm.

When these syndromes are caused by antibodies generated in response to the tumor, the antibodies are either to membrane-associated tumor antigens or to intracellular tumor antigens. These antibodies react both to the tumor antigen and to an epitope present in normal nerve tissue. When the causative antibody is a tumor-produced antibody, it attacks nerve tissue directly.

The tumor antigens most likely to induce harmful antibody responses are membrane proteins such as neurotransmitter receptors or voltage-gated ion channels. Dr. Pestronk said that, in such cases, the resulting paraneo-plastic syndrome tends to be a membrane dysfunction, often including focal evidence of damage to the nerve or muscle cell.

These syndromes are often treatable with plasma exchange and corticosteroids. Examples include Lambert-Eaton myasthenic syndrome, autonomic neuropathy, Isaac’s neuromyotonia, and myasthenia gravis. Associated cancer types include SCLC, thymoma, and lymphoma.

Paraneoplastic syndromes due to tumor-secreted antibodies are determined by antigen binding patterns. Tumor antibodies against myelin-associated glycoprotein typically cause demyelination neuropathies, which affect sensory more often than motor function. Antibodies against GM-1 ganglioside more often affect motor function and may include a conduction block along motor axons.

Dr. Pestronk said that treatment of these syndromes is more difficult and often requires drugs that reduce titers of associated antibodies, such as cytotoxic agents, or that interfere with antibody action, such as IV immunoglobulin G (IVIG). “The one treatment that seems to be effective is a combination of plasma exchange with intravenous cyclophosphamide over several months,” he said.

Peripheral Effects

The main autoimmune disorders that affect the neuromuscular junction can all occur as paraneoplastic syndromes, said John Newsom-Davis, MD, of the Institute of Molecular Medicine, University of Oxford, UK. “Thymoma is present in 10% of myasthenia gravis patients and in 15% of autoimmune neuromyotonia patients. SCLC is present in about 50% of patients with Lambert-Eaton myasthenic syndrome,” Dr. Newsom-Davis said.

Symptoms and the associated antibody appearance can precede tumor clinical presentation by up to 5 years. The damaging antibodies in these disorders bind to the muscle acetylcholine receptor, neuronal voltage-gated potassium channels, or presynaptic P/Q-type voltage-gated calcium channels at the neuromuscular junction and at postganglionic autonomic synapses. “These ion channels have large extracellular domains and lack the protection of the blood-brain or blood-nerve barrier,” Dr. Newsom-Davis pointed out.

Symptoms of these syndromes may include muscle twitches, cramps, stiffness, weakness, increased sweating, pares-thesias, mood change, or insomnia. “The muscle twitches are easy to miss if you don’t strip the patient and look carefully,” he added. Plasma exchange is often useful in relieving these symptoms, which will also usually improve with successful tumor treatment.

The tumor is driving the immune response, but is the immune response helping the patient? Apparently so. Dr. Newsom-Davis reported that the survival curve is significantly improved in SCLC patients who also develop Lambert-Eaton myasthenic syndrome.

Retinal Dysfunction

Cancer-associated retinopathy is a paraneoplastic disorder associated with SCLC, in which antibodies against retinal rods and cones cause visual problems. John L. Keltner, MD, said that these can cause a remarkable devastation of retinal structure. Dr. Keltner is chair of the Department of Ophthalmology, University of California Davis Medical Center.

Symptoms include unexplained visual loss, photopsias (flashes of light), poor night vision, abnormal visual acuity, color vision abnormalities, and ring scotomas, but few signs of inflammation. Dr. Keltner described the syndrome as “like an accelerated retinitis pigmentosa” and said that visual loss occurs usually over months and frequently precedes the discovery of the cancer. Symptoms often stabilize with steroid treatment.

Melanoma-associated retinopathy usually develops after cutaneous melanoma. It includes characteristic shimmering, flickering, or pulsating flashes of light, often associated with progressive loss over several months. Both of these syndromes are difficult to treat, he said. Steroids, plasma exchange, and IVIG have been tried, with variable results, he said.

Most paraneoplastic syndromes that affect the peripheral nervous system are associated with antigens located on the cell surface. Removal of the antibodies with plasma exchange often improves the neurological problem. CNS paraneoplastic syndromes, on the other hand, are usually associated with antibodies against cytoplasmic antigens and are much more difficult to treat. “In general, these syndromes respond poorly to treatment, and the corresponding antibodies, rather than perceived as pathogenic, should be considered markers of syndromes associated with specific neoplasms,” said Josep Dalmau, MD, PhD, of Memorial Sloan-Kettering Cancer Center.

CNS syndromes, including opsoclonus, ataxia, limbic and brainstem encephalitis, and cerebellar degeneration, have all been associated with tumors. The target antigens include CDR34, CDR62, amphiphysin, and the nuclear antigens Hu and Yo. Associated neoplasms include SCLC, ovarian cancer, and breast cancer. Dr. Dalmau said that these syndromes are less responsive to treatment than peripheral nerve syndromes, possibly because the neurological damage occurs earlier and is irreversible.