Paraneoplastic Neurologic Syndromes Present Before Testicular Germ Cell Tumor Diagnosis, Study Shows

In a newly published retrospective cohort study, findings showed that patients with testicular germ cell tumors (TGCTs) frequently exhibited paraneoplastic neurologic syndromes (PNSs) prior to their cancer diagnosis, which were often associated with specific neural autoantibody biomarkers such as Kelch-like protein 11 (KLHL11), leucine zipper 4 (LUZP4) antibodies, and Ma2-IgG. These results suggest that timely diagnosis and treatment of PNSs may mitigate substantial long-term neurological disabilities and improve cancer outcomes.¹

Out of 49 patients (median age, 41.0 years [IQR, 32.5-47.5]) included in the study, most (n = 33) reported experiencing PNS symptoms before being diagnosed with TGCT. Among the patients included in the study, 45 had definite PNS and 4 had probable PNS, as determined by the PNS CARE score. Findings revealed that the most frequently observed symptoms were ataxia (n = 31), diplopia (n = 29), sensorineural hearing loss (n = 22), and vertigo (n = 20).

“This cohort study found that 80% of patients had neurological symptoms before TGCT diagnosis. Thus, recognition of early signs and symptoms of PNS in young and middle-aged patients should alert neurologists not only to test for KLHL11-IgG, LUZP4-IgG, and Ma2-IgG, but also to search for any underlying occult malignant entity, especially TGCTs,” lead author Ehab Harahsheh, MBBS, assistant professor of neurology at the University of Arizona, and colleagues wrote.¹ “Early recognition and diagnosis of PNS in patients with TGCT by oncologists via testing for these antibodies may reduce long-term neurological dysfunction, a major cause of morbidity and mortality in our cohort, especially with the favorable TGCT outcomes.”

For the current study, researchers aimed to investigate the oncological, neurological, and serological profiles of patients with TGCT and PNS. Authors noted that the analysis included patients aged 18 years or older with histopathologically confirmed diagnosis of TGCT, or regressed TGCT, and PNS. These patients completed evaluation and treatment at Mayo Clinic between January 1, 1990, to March 30, 2023. Additionally, eligible patients with TGCT and PNS, serum and/or cerebrospinal fluid were assessed for neural antibodies, including KLHL11-IgG, LUZP4-IgG, and Ma2-IgG. Investigators reviewed patients’ records for demographic, oncological, and neurological data whenever available.

Most TGCT cases were seminomas (n = 33), with the remainder (n = 9) consisting of NSGCT or regressed TGCTs (n = 7). Notably, results showed that seminomas were more often associated with ataxia, sensorineural hearing loss, and vertigo, whereas nonseminomatous germ cell tumors (NSGCTs) were more frequently associated with seizures and sleep disturbances.

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Over a median follow-up of 33.0 months (IQR, 6.5-64.0) from TGCT diagnosis to final evaluation, 80% of patients achieved either cure (n = 18) or remission (n = 21), while 6 patients experienced tumor relapses (12%), and 9 patients died (18%). Authors noted that no deaths were attributed to TGCTs; 6 patients died of PNS, 1 died of myocardial infarction, and the cause of death was unclear for 2 patients. 

All told, 94% of patients tested positive for neural autoantibodies. The most frequently identified antibody was KLHL11-IgG (n = 32), including 20 cases alone and 12 cases coexisting with LUZP4-IgG, followed by Ma2-IgG (n = 9), including 1 case coexisting with LUZP4-IgG, and LUZP4-IgG alone (n = 5). Among patients with KLHL11-IgG and LUZP4-IgG, seminomas were present in 72% (n = 23) and 78% (n = 14), respectively. In contrast, 78% of patients with Ma2-IgG (n = 7) had NSGCTs. Furthermore, KLHL11-IgG and Ma2-IgG were associated with seminomas (OR, 8.06; 95% CI, 1.42-45.46; P = .02) and NSGCTs (OR, 54.25; 95% CI, 6.48-454.07; P <.001), respectively.

Additional findings demonstrated that KLHL11-IgG was associated with sensorineural hearing loss (OR, 12.50; 95% CI, 2.43-64.43; P <.001) and tinnitus (OR, 12.44; 95% CI, 1.47-105.52; P = .006), whereas Ma2-IgG was associated with seizures (OR, 11.33; 95% CI, 2.21-58.15; P = .004) and sleep disturbances (OR, 43.17; 95% CI, 6.06-307.41; P <.001). Moreover, only 8 patients showed improvement of their PNS (16%), whereas 21 had stabilization (43%) and 20 had progression (41%), despite immunomodulatory treatment.

“The type of neurological manifestation and neural antibodies varied according to the TGCT subtype. Thus, the presence of neurological manifestations and neural antibodies may not only indicate an underlying occult TGCT but could also suggest the tumor histology. Potential study limitations include selection bias and referral bias. Although most patients achieved positive cancer outcomes, many faced long-term neurological disability,” Harahsheh et al noted.¹

At the 2025 American Academy of Neurology (AAN) Annual Meeting, held April 5-9, in San Diego, California, Feinberg School of Medicine neuro-oncology experts Ditte Primdahl, MD, and Shailee Samir Shah, MD, spoke with NeurologyLive^® to underscore the field’s growing understanding of PNS in the context of cancer immunotherapies. They emphasized the critical need for practical screening algorithms in community and nonacademic settings. The conversation highlighted the nuanced decision-making in managing cancer treatment when neurologic symptoms arise, emphasizing the need for interdisciplinary coordination in addressing these complex, overlapping conditions.

REFERENCES
1. Harahsheh E, Hammami MB, Gupta P, et al. Testicular Cancer-Associated Paraneoplastic Neurologic Syndromes. JAMA Netw Open. 2025;8(10):e2538584. Published 2025 Oct 1. doi:10.1001/jamanetworkopen.2025.38584