Clinical spectrum, malignancy association and immunotherapy outcomes in anti-Zic4 antibody-positive patients: A case series and systematic review
Milad Javidan, Armin Adibi, Fereshteh Ashtari, Vahid Shaygannejad, Iman AdibiBackground
Anti-Zic4 antibodies are classically associated with paraneoplastic neurological syndromes, particularly small-cell lung cancer (SCLC) and cerebellar degeneration. However, the broader neurological spectrum and outcomes remain incompletely defined.
Objectives
To characterize clinical manifestations, malignancy, antibody detection, treatment responses, and outcomes of anti-Zic4 antibody–positive patients, and to explore differences between patients with identified malignancy and those remaining tumor-negative during prolonged follow-up.
Design
Retrospective case series and systematic literature review.
Data sources and Methods
We retrospectively analyzed seven patients with anti-Zic4 reactivity detected by dot blot, all with cerebrospinal fluid (CSF) positivity. A PRISMA-guided search of PubMed, Scopus, Web of Science, and Embase identified 81 patients from 21 studies. Combined with our series, 88 patients were analyzed. Exploratory comparisons used two-sided Fisher’s exact tests.
Results
Malignancy was identified in 76/88 (86.4%), most commonly SCLC (61/76, 80.3%). Cerebellar and extracerebellar manifestations occurred with comparable frequency. Among 27 individually described cases, encephalopathy was present in 15 (55.6%), and abnormal neuroimaging and inflammatory cerebrospinal fluid findings occurred in 12/27 (44.4%) and 11/27 (40.7%), respectively. Tissue-based antibody confirmation was documented in 7/88 (8.0%), while 80/88 (90.9%) had blot-based positivity without tissue confirmation. Encephalopathy was more frequent in five patients with ≥24 months of tumor-negative follow-up than in 76 patients with identified malignancy (100% vs 30.3%; p=0.004); with similar findings in PND sensitivity analyses. Additional neuronal antibodies were less frequent in the prolonged tumor-negative group (20% vs 70.3%, p=0.039; 20% vs 83.3%, p=0.007 in the Bataller sensitivity analysis). All five prolonged tumor-negative patients showed mild-to-moderate improvement with immunotherapy.
Conclusions
Anti-Zic4 positivity is strongly associated with malignancy, particularly SCLC, but encompasses a broader neurological spectrum than classical cerebellar syndromes. Prolonged tumor-negative cases may represent a distinct clinical course, but current evidence is insufficient to establish a separate non-paraneoplastic phenotype. Systematic cancer surveillance, standardized antibody testing and long-term follow-up are needed.