Defining LEMS

David Gerber, MD: Hello and welcome to this OncLive® My Treatment Approach program on “Lambert-Eaton Myasthenic Syndrome and Associated Cancers.” I’m David Gerber, professor of internal medicine within the hematology/oncology division and associate director of clinical research in the Simmons Comprehensive Cancer Center at [University of Texas] Southwestern Medical Center in Dallas, Texas. I’m happy to discuss this topic and case scenarios with my colleague, Dr Steven Vernino, distinguished teaching professor and executive vice chair for academic affairs in the Department of Neurology at UT Southwestern Medical Center. Before we review the cases, I want to go over information on the disease and testing. Could you start by defining Lambert-Eaton myasthenic syndrome, or LEMS?

Steven Vernino, MD, PhD: Lambert-Eaton myasthenic syndrome is a type of neuromuscular disorder that affects the communication between nerves and muscles. This was first described in the 1950s by various people, but most notably by [Edward] Lambert and [Lee] Eaton, who were neurologists at the Mayo Clinic. Lambert-Eaton myasthenic syndrome characteristically presents as fatigable weakness; patients often come in complaining of weakness in their lower limbs, around their hips, and they have trouble walking, getting up from a chair, or climbing the stairs due to weakness in their proximal legs. They often complain of generalized fatigue, which is a nonspecific symptom, but particularly when they try to do things. These complaints are like many other neuromuscular diseases that we see in neurology. Patients with Lambert-Eaton myasthenic syndrome also complain of other vague symptoms, including things like dry mouth, constipation, and others. It can be a difficult diagnosis, but it’s an important one to think about and to diagnose.

There are different types of Lambert-Eaton myasthenic syndrome. We’re going to discuss Lambert-Eaton that’s associated with cancers, or the paraneoplastic form of LEMS, but this can also occur in a nonparaneoplastic or autoimmune scenario. LEMS is a rare disease; it’s considered to be about 10 times less common than myasthenia gravis, which is the more recognizable and appreciated disorder of this neuromuscular junction. It can occur frequently in patients with small cell lung cancer. It’s estimated that up to 2% to 3% of all patients with small cell lung cancer have Lambert-Eaton myasthenic syndrome, which makes it more common among the rare paraneoplastic neurological syndromes. About half of LEMS cases are cancer-related, and the other half are noncancer autoimmune diseases. Having small cell lung cancer is a major risk factor for getting Lambert-Eaton syndrome, and those patients tend to be older men who have a smoking history; those were the patient types who were originally described by Lambert and Eaton. If we see younger patients, meaning middle-aged people and women, we start to think about nonparaneoplastic or autoimmune LEMS, particularly if the patient is a nonsmoker and has no other cancer risk factors. David, can you talk more about the association with cancer and LEMS and paraneoplastic syndromes?

David Gerber, MD: My perspective is skewed because I am a thoracic medical oncologist; most of my patients have lung cancer, including small cell lung cancer. Any of the patients in my practice who have paraneoplastic LEMS have lung cancer. I know it can also be seen rarely in other cancers, maybe gynecological cancers or lymphomas, but small cell lung cancer will be the dominant cause in terms of a cancer association. It raises the question, what is the link mechanistically or biologically between small cell lung cancer and LEMS? For me, it helps to think of this condition as an autoimmune process. When it comes to paraneoplastic conditions, one category of them is autoimmune, including most of the neurologic ones. Something is happening in these patients when they have a cancer diagnosis that’s making their body attack healthy, normal cells, tissues, and organs, including the nervous system. I break down the reasons for that happening into a couple of different possibilities. The first is that the cancer produces a protein that resembles part of the nervous system, that’s the case for small cell lung cancer; it’s almost cross-reactivity or tricking the immune system. The second, this is far less common, is that a tumor could contain nervous system components. An example of that is a teratoma; these are rare tumors that can grow slowly and quite large and can feature normal types of tissue like hair, teeth, and nervous system tissues. Then there are the types of tumors that involve organs that are usually involved in the regulation of the immune system; that’s the thymus and thymoma, why we see myasthenia gravis.

Lastly, there are the tumors that involve the production of immunoglobulins or antibodies, and that can be myeloma or lymphoma, which is potentially why we see LEMS with lymphoma cases. Why is it that small cell lung cancer tricks the body into thinking that it’s part of the nervous system? Neuroendocrine tumors look like and have antigen similar to the nervous system. When we diagnose small cell lung cancer, besides the pathologists looking under the microscope, they perform special immunohistochemical staining, or IHC. One of the most frequently used stains is CD56, which is the same as NCAM, neural cell adhesion molecule. This is why as small cell lung cancer develops, with those cells looking similar to the body’s immune system as the nervous system components, that you can not only get LEMS, but multiple other autoimmune paraneoplastic conditions affecting other components of the nervous system.

Transcript edited for clarity.