Background: Squamous cell carcinoma metastatic to cerebrospinal fluid (CSF) is a rare diagnosis on cytology, and thereby more challenging in comparison to an adenocarcinoma metastatic to CSF. We recently encountered a case of metastatic squamous cell carcinoma in CSF. The primary site was unknown. A review of the literature was performed to understand why this is a rare diagnosis in cytology. Case: A 56-year-old male was diagnosed with a keratinizing squamous cell carcinoma involving multiple lymph nodes in the neck. On extensive clinical and radiologic evaluation, a primary could not be identified. Subsequently, the patient presented with sudden loss of vision (in the right eye), nausea and vomiting. MRIs of the lumbar spine and optic nerve were suggestive of leptomeningeal and perineural seeding, respectively. Cytologic evaluation of CSF revealed a few atypical, round hyperchromatic cells which were confirmed as epithelial cells through immunocytochemistry for a broad-spectrum keratin. The diagnosis of metastatic carcinoma consistent with squamous cell carcinoma was rendered. Conclusion: Definitive diagnosis of metastatic squamous cell carcinoma is challenging unless clinical evidence is present. Besides other factors, the mode of spread to CSF may be responsible for this less common diagnosis.

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