Clinical Characteristics of Patients with Motor Neuron Disease and Concurrent Tumors
Motor neuron disease (MND) is a progressive and fatal neurodegenerative disorder that affects both upper and lower motor neurons, as well as the pyramidal tract. Despite extensive research, the etiology of MND remains largely unknown, and treatment options are limited. One rare form of MND is paraneoplastic syndrome (PNS), which mimics the clinical symptoms of MND and is associated with various types of cancer, including breast cancer, lung cancer, and lymphoma. The relationship between MND and cancer is complex, with some epidemiological studies suggesting no association between site-specific cancers and the risk of amyotrophic lateral sclerosis (ALS), while others indicate a reduced overall risk of cancer in ALS patients. However, the prevalence of tumors in Chinese MND patients and the clinical characteristics of those with concurrent tumors remain unclear.
To address this gap, a study was conducted at Peking University Third Hospital (PUTH) from January 2010 to December 2016, involving 1751 patients diagnosed with MND according to the revised El Escorial criteria. These patients were followed up every three months through phone or face-to-face interviews, with the endpoint defined as death or the need for invasive mechanical ventilation. The study was approved by the Ethics Committee of PUTH, and written informed consent was obtained from all participants.
Among the 1751 MND patients, 28 (1.6%) were found to have concurrent tumors, a proportion lower than the 8.7% or 10.1% reported in other studies. This discrepancy raised concerns about potential missed diagnoses of tumors in the study population. The most common malignancies observed were lung cancer (n = 8), lymphoma (n = 3), breast cancer (n = 3), thyroid cancer (n = 2), esophageal cancer (n = 2), and gastric cancer (n = 2). One patient had both esophageal and kidney cancer. The prevalence of lung cancer, breast cancer, and lymphoma in MND patients aligns with findings from previous studies. Notably, thyroid cancer has been rarely reported in association with MND, with only one case of paraneoplastic MND linked to thyroid cancer documented in the literature.
The study revealed that 64.3% (n = 18) of the patients with concurrent tumors were diagnosed with cancer after the initial diagnosis of MND, with a median interval of 20 months between the two diagnoses. In addition to motor symptoms, 14.3% (n = 4) of the patients exhibited sensory impairments, including severe pain, while another 14.3% (n = 4) had cognitive or affective impairments, and 7.1% (n = 2) experienced bowel or bladder dysfunction. These findings suggest that tumors may extensively impair motor, sensory, and advanced cortical functions, consistent with the view that MND is a multisystem disease with extra-motor involvement. Previous studies have reported that 15% to 45% of MND patients exhibit executive and behavioral disorders at various stages of the disease, with symptoms such as memory loss, anxiety, and depression being common. Additionally, more than 60% of MND patients experience sensory symptoms, including paresthesia and pain, and autonomic dysfunction occurs in about one-third of patients, manifesting as sweating dysfunction, urinary urgency, and constipation.
The study also highlighted the challenges in diagnosing tumors in MND patients. Only 18% of the patients underwent lumbar puncture, and the positive rates for tumor markers (16.7%) and onconeuronal antibodies (5.3%) were low, indicating insufficient etiological screening in clinical practice and the need for more sensitive biomarkers to aid in early tumor detection.
A comparison between MND patients with and without tumors revealed significant differences in onset age. The mean onset age for patients without tumors was 51.5 years, significantly lower than the 61.9 years observed in patients with tumors. To account for this discrepancy, propensity score matching (PSM) was used to match patients without tumors to those with tumors in a 4:1 ratio based on sex and onset age. The median follow-up time for patients with tumors was 37 months, with 46.4% (n = 13) reaching the endpoint (death or tracheotomy). In contrast, the median follow-up time for patients without tumors was 25.5 months, with 49.1% (n = 55) reaching the endpoint. Kaplan-Meier survival analysis showed that MND patients with tumors had significantly longer survival times than those without tumors (P = 0.006). A Cox proportional hazards model further confirmed that the presence of tumors was associated with longer survival, even after controlling for diagnostic delay, interval to the second segment, and treatment of MND (hazard ratio: 0.216, 95% confidence interval: 0.065–0.715, P = 0.012).
Several factors may contribute to the longer survival observed in MND patients with tumors. First, some patients presented with flail arm syndrome (FAS) or flail leg syndrome, and others met the criteria for isolated bulbar ALS (IBALS), conditions that tend to have a better prognosis. Second, some patients stabilized after tumor-targeted therapy or immunotherapy, suggesting that tumor-induced autoimmunity or other mechanisms, such as oxidative stress, apoptosis, and methylation, may play a role in altering the disease course compared to degenerative MND.
Among the 28 patients with concurrent tumors, one was diagnosed with definite PNS according to Graus’ diagnostic criteria, and 12 were classified as possible PNS. The patient with definite PNS tested positive for the antibody amphiphysin in blood but negative in cerebrospinal fluid, and neurological symptoms worsened after surgical resection of lung cancer, which is atypical for PNS. Among the 12 possible PNS cases, nine could be diagnosed with typical ALS, two with progressive bulbar palsy, and one with IBALS or FAS. Three patients exhibited symptoms beyond the motor system, including cognitive and sensory impairments. The most common tumors in these patients were lung cancer (n = 4), hematologic tumors (n = 3), thyroid cancer (n = 2), breast cancer (n = 1), prostate cancer (n = 1), and gastric cancer (n = 1). Only two patients developed MND symptoms after the diagnosis of tumors.
In conclusion, this study provides valuable insights into the clinical characteristics of MND patients with concurrent tumors, highlighting differences in clinical manifestations and disease progression compared to degenerative MND. Although cases of MND with concurrent tumors are rare, further research is necessary to elucidate the underlying mechanisms and improve early diagnosis and treatment strategies.
doi.org/10.1097/CM9.0000000000001207
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