Objective: To determine the frequency and range of paraneoplastic neurologic disorders (PNDs) and neuronal antibodies in small cell lung carcinoma (SCLC).Methods: Two hundred sixty-four consecutive patients with biopsy-proven SCLC were recruited at the time of tumor diagnosis. All patients underwent full neurologic examination. Serum samples were taken prior to chemotherapy and analyzed for 15 neuronal antibodies. Thirty-eight healthy controls were analyzed in parallel.Results: PNDs were quite prevalent (n 5 24, 9.4%), most frequently Lambert-Eaton myasthenic syndrome (3.8%), sensory neuronopathy (1.9%), and limbic encephalitis (1.5%). Eighty-seven percent of all patients with PNDs had antibodies to SOX2 (62.5%), HuD (41.7%), or P/Q VGCC (50%), irrespective of their syndrome. Other neuronal antibodies were found at lower frequencies (GABAb receptor [12.5%] and N-type VGCC [20.8%]) or very rarely (GAD65, amphiphysin, Ri, CRMP5, Ma2, Yo, VGKC complex, CASPR2, LGI1, and NMDA receptor [all ,5%]).
Conclusions:The spectrum of PNDs is broader and the frequency is higher than previously appreciated, and selected antibody tests (SOX2, HuD, VGCC) can help determine the presence of an SCLC. Neurology ® 2015;85:235-239 GLOSSARY HC 5 healthy control; LE 5 limbic encephalitis; LEMS 5 Lambert-Eaton myasthenic syndrome; PCD 5 paraneoplastic cerebellar degeneration; PEM 5 paraneoplastic encephalomyelitis; PND 5 paraneoplastic neurologic disorder; SCLC 5 small cell lung carcinoma; SN 5 sensory neuronopathy.A paraneoplastic neurologic disorder (PND) results from the indirect effect of a tumor on the nervous system or muscle without local invasion or metastasis. PNDs are often associated with antibodies that bind to proteins shared between the tumor and the nervous system.
Improved SCLC tumor survival seen in patients with LEMS and SCLC may not be due solely to lead time bias, given that survival advantage remains after allowing for other prognostic factors and that the same degree of survival advantage is not seen in patients with paraneoplastic neurologic syndromes other than LEMS presenting before SCLC diagnosis.
Paraneoplastic neurological syndromes can be associated with the presence of onconeural antibodies. These antibodies are the result of an immune response against a tumour that is ectopically expressing a neuronal antigen. The 'classical' onconeural antibodies (anti-Hu, Yo, Ma2, CRMP-5, amphiphysin and Ri) are directed against intracellular antigens and are strongly associated with underlying malignancy. By contrast, onconeural antibodies directed against cell surface antigens (eg, anti-NMDA, VGKC, AChR) have a weaker tumour association. This article gives a practical overview of the tumour associations, and the neurological associations, of the onconeural antibodies. There is also guidance on how to investigate occult malignancy in antibody positive cases.
PurposeFavourable small cell lung carcinoma (SCLC) survival outcomes have been reported in patients with paraneoplastic neurological disorders (PNDs) associated with neuronal antibodies (Neur-Abs), but the presence of a PND might have expedited diagnosis. Our aim was to establish whether neuronal antibodies, independent of clinical neurological features, correlate with SCLC survival.Experimental Design262 consecutive SCLC patients were examined: of these, 24 with neurological disease were excluded from this study. The remaining 238 were tested for a broad array of Neur-Abs at the time of cancer diagnosis; survival time was established from follow-up clinical data.ResultsMedian survival of the non-PND cohort (n = 238) was 9.5 months. 103 patients (43%) had one or more antigen-defined Neur-Abs. We found significantly longer median survival in 23 patients (10%) with HuD/anti-neuronal nuclear antibody type 1 (ANNA-1, 13.0 months P = 0.037), but not with any of the other antigen-defined antibodies, including the PND-related SOX2 (n = 56, 24%). An additional 28 patients (12%) had uncharacterised anti-neuronal nuclear antibodies (ANNA-U); their median survival time was longer still (15.0 months, P = 0.0048), contrasting with the survival time in patients with non-neuronal anti-nuclear antibodies (detected using HEp-2 cells, n = 23 (10%), 9.25 months). In multivariate analyses, both ANNA-1 and ANNA-U independently reduced the mortality hazard by a ratio of 0.532 (P = 0.01) and 0.430 (P<0.001) respectively.ConclusionsANNAs, including the newly described ANNA-U, may be key components of the SCLC immunome and have a potential role in predicting SCLC survival; screening for them could add prognostic value that is similar in magnitude to that of limited staging at diagnosis.
Antibodies to SOXB1 proteins in patients with paraneoplastic disorders are associated with small-cell lung cancer (SCLC), particularly in Lambert-Eaton myasthenic syndrome (LEMS). We aimed to establish if SOX2 antibodies could be used to identify SCLC and other tumours found in a range of paraneoplastic disorders and controls.
SOX2 antibodies were detectable in 61% of patients with LEMS-SCLC, and in other paraneoplastic disorders, such as opsoclonus-myoclonus and paraneoplastic cerebellar degeneration, only when there was an underlying SCLC.
SOX2 antibodies are specific (>90%) markers for SCLC, but are rarely found in patients with other tumours, whether neurological symptoms are present or not.
Paraneoplastic neurological syndromes can be associated with the presence of onconeural antibodies. These antibodies are the result of an immune response against a tumour that is ectopically expressing a neuronal antigen. The 'classical' onconeural antibodies (anti-Hu, Yo, Ma2, CRMP-5, amphiphysin and Ri) are directed against intracellular antigens and are strongly associated with underlying malignancy. By contrast, onconeural antibodies directed against cell surface antigens (eg, anti-NMDA, VGKC, AChR) have a weaker tumour association. This article gives a practical overview of the tumour associations, and the neurological associations, of the onconeural antibodies. There is also guidance on how to investigate occult malignancy in antibody positive cases.
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