The term paraneoplastic syndromes refers to symptoms or signs resulting from damage to organs or tissues that are remote from the site of a malignant neoplasm or its metastases. Paraneoplastic syndromes can affect most organs and tissues. Widely known examples include cancer cachexia, hypercalcemia, Cushing’s syndrome and Trousseau’s syndrome.
Most of these paraneoplastic syndromes occur because the tumor secretes substances that mimic normal hormones or that interfere with circulating proteins. A few paraneoplastic neurologic disorders are caused by similar mechanisms (e.g., carcinoid myopathy and encephalopathy).
However, most or all paraneoplastic neurologic disorders are immune-mediated. The cancers causing paraneoplastic neurologic disorders are often asymptomatic and sometimes occult; it is the neurologic symptoms that take the patient to the doctor. The combination of an indolent tumor and severe neurologic disability suggests effective antitumor immunity coupled with autoimmune brain degeneration. Paraneoplastic neurologic disorders can affect any part of the nervous system (see Table below ). Some of them affect only a single area (e.g., limbic encephalitis) or a single cell type (e.g., the Purkinje cells of the cerebellum). In other instances, multiple levels of the nervous system are involved (e.g., encephalomyeloradiculitis).
Most symptomatic paraneoplastic syndromes are rare, affecting perhaps 0.01 percent of patients with cancer. The symptoms and signs of paraneoplastic syndromes are diverse, but certain features are common. The neurologic disorder usually appears before the cancer has been identified. In many instances an initial search for cancer is unrewarding; the tumor is found months or even a few years after the appearance of the neurologic syndrome.
Whole-body positron-emission tomography may be the best screening method for locating the occult cancer.
Paraneoplastic neurologic disorders are usually severe, often disabling, and sometimes lethal.
Examination of cerebrospinal fluid reveals a mild pleocytosis (30 to 40 white cells per cubic millimeter), a slightly elevated protein level (50 to 100 mg per deciliter), and an elevated IgG level. Pleocytosis is usually apparent only early in the course of the disease and disappears within several weeks to months.
The elevated IgG level may, however, persist. Analysis of cerebrospinal fluid cells in patients with paraneoplastic cerebellar degeneration through fluorescent-activated cell sorting has revealed that the predominant cell type (over 75 percent) is T cells, with a small component (less than 10 percent) of B cells and Natural Killer cells.
Perhaps most important diagnostically, many patients with paraneoplastic syndromes have antibodies in their serum (and cerebrospinal fluid) that react with both the nervous system and the underlying cancer. The identification of these antibodies and their target neural antigens has substantially advanced the ability to make an early diagnosis and has led to the concept that paraneoplastic neurologic disorders are immune-mediated. Although there is considerable overlap, each of these antibodies is associated with a narrow spectrum of clinical syndromes and a restricted subgroup of cancers . The antibodies, some of which named using the first two letters of the surname of the index patient, are highly specific for identifying a patient with neurologic disability who
has a paraneoplastic syndrome. These antibodies also suggest the site of the underlying cancer. For example, the presence of anti-Yo antibodies in the serum of a woman with cerebellar symptoms is virtually conclusive evidence that she has paraneoplastic cerebellar degeneration and gynecologic, usually ovarian, cancer.
Unfortunately, not all patients with paraneoplastic syndromes have identifiable antibodies in their serum. Whether this is a technical fault in detection or whether some paraneoplastic neurologic disorders are not immune-mediated is not known.
In most cases of paraneoplastic syndromes associated with antibodies, the antigen has been identified and the gene coding for the antigen has been cloned and sequenced (see Table 2)
Some of these antigens are expressed by all tumors of a given histologic type, whether or not the patient mounts an immune response against them. Other tumors rarely express such antigens unless the cancer causes a paraneoplastic neurologic disorder. Failure to find the antigen in the cancer of a patient with paraneoplastic antibodies should prompt a search for a second cancer.
The Autoimmune Model Of Pathogenesis
Currently, it is thought that most or all paraneoplastic neurologic disorders are immune-mediated
The mechanism entails ectopic expression by a tumor of an antigen that normally is expressed exclusively in the nervous system. Some of these so-called onconeural antigens are also expressed in the normal testis, an organ that is, like the brain, an immunologically privileged site. The tumor antigen is identical to the neural antigen, but for unknown reasons the immune system identifies it as foreign and mounts an immune attack. The immune attack controls the growth of the cancer and may in a few instances obliterate it. However, the antibodies and cytotoxic T cells that are specific for the tumor antigen are not sufficient to cause the neurologic disease unless they cross the blood– brain barrier and react with neurons expressing the onconeural antigen (Table 3).
Tumor Immunity In Paraneoplastic Syndromes
Onconeural antigens are present in the tumor in all patients with antibody-positive paraneoplastic neurologic disorders and in many patients without such disorders. Moreover, the genes for these antigens are not mutated in tumor cells.
Thus, paraneoplastic neurologic syndromes cannot be attributed to the infrequency of expression of the relevant tumor antigens or to mutations in the genes encoding these antigens. The tumor is often occult, and the neurologic disorder typically precedes the diagnosis of the tumor.
For example, patients with the Hu paraneoplastic syndrome typically harbor small-cell lung
cancers that are limited to single nodules, despite the fact that most small-cell lung cancers (over 60 percent) are widely metastatic at diagnosis. In a few instances, unequivocal paraneoplastic syndromes may follow identification and even treatment of the tumor, and may sometimes herald a relapse. The histologic features of tumors in paraneoplastic neurologic disorders do not differ from those of other tumors, except that the tumors may be heavily infiltrated with inflammatory cells. Many reports suggest that patients with paraneoplastic neurologic disorders have a better prognosis than patients with histologically identical tumors that are not associated with paraneoplastic neurologic disorders. The improved prognosis is not simply a result of earlier diagnosis of the cancer because the neurologic disease has led to a search for cancer. Patients with low titers of anti-Hu antibodies but without paraneoplastic disorders also have more limited small-cell lung cancer than patients who do not have the antibodies.
The Nervous System
The presence of antigen-specific cytotoxic T cells in paraneoplastic neurologic disorders was clearly documented after a patient with acute paraneoplastic cerebellar degeneration and anti-Yo antibodies was found to have activated T cells in her blood that were able to lyse target cells presenting the Yo (alsocalled cdr2) antigen in vitro.Subsequent studies in chronically ill patients with paraneoplastic cerebellar degeneration have used autologous antigen-presenting cells (dendritic cells) to reactivate responses to the cdr2 antigen in memory cytotoxic T cells. Such reactivated responses have been elicited in all patients with paraneoplastic cerebellar degeneration whose T cells were tested for the phenomenon. These studies have been complemented by reports of a limited Vb chain T-cell repertoire in patients with the Hu syndrome (the Vb is one of the two chains, Vb and Va, of the T-cell receptor). Taken together, the evidence indicates that T-cell responses have an important role in paraneoplastic neurologic disorders. Antibodies in paraneoplastic neurologic disorders react with the portion of the nervous system that is responsible for the clinical symptoms — for example, anti–Purkinje-cell antibodies occur in patients with paraneoplastic cerebellar degeneration. In many instances, the reaction is more widespread than the clinical findings. In paraneoplastic neurologic disorders affecting the brain, relatively high titers of the antibody in the cerebrospinal fluid (relative to total IgG) indicate that the antibody is synthesized within the brain, presumably by specific B cells that have crossed the blood–brain barrier.
One report described the presence of anti-Hu antibodies within neuronal nuclei of the central nervous system in patients who died of their paraneoplastic syndromes.
Although some believe this finding to be an artifact, antibodies to doublestranded DNA, the hallmark of systemic lupus erythematosus, have been found within the nuclei of cells in patients with systemic lupus erythematosus.
Antibodies and Cytotoxic T Cells
The relative roles of humorally mediated immunity (antibodies) and cellular immunity (T cells) in paraneoplastic neurologic disorders are unresolved. This uncertainty is complicated by the fact that different paraneoplastic neurologic disorders may have different underlying mechanisms. When the target antigens are cell-surface receptors, as in the Lambert–Eaton myasthenic syndrome, myasthenia gravis, and a rare form of paraneoplastic cerebellar degeneration, antibodies appear to have the predominant role.
Protection Against The Tumor
It is not known whether the antitumor immune response in paraneoplastic neurologic disorders can be harnessed to treat tumors without damaging the nervous system. In the current model of paraneoplastic neurologic disorders (Fig. 2), apoptosis of tumor cells triggers an antitumor immune response. Indeed, it has been shown that apoptotic tumor cells in paraneoplastic neurologic disorders are a potent means of activating tumor-specific T cells.
Such killer T cells could trigger a feedback loop by inducing apoptosis and hence amplification of the antitumor immune response. These observations suggest that understanding the mechanisms that trigger effective tumor immune responses in patients with paraneoplastic neurologic disorders may have an important role in developing successful approaches to tumor immunotherapy.