To describe a case of leptomeningeal carcinomatosis of lung origin initially misdiagnosed as neurosyphilis based on false-positive CSF-VDRL. 

Leptomeningeal carcinomatosis occurs in around 5% of patients with metastatic cancer, particularly breast and lung cancer, and is associated with worse prognosis. Early diagnosis is critical and requires cerebrospinal fluid (CSF) analysis showing malignant cells. Leptomeningeal carcinomatosis can present with neurological and systemic symptoms similar to CNS infections, such as neurosyphilis with a subacute time course, and similar radiographic findings. There are less than 20 published cases of false-positive CSF-VDRL with eventual diagnosis of leptomeningeal carcinomatosis associated with primary lung cancer. 

A 71-year-old man with a history of non-small cell lung cancer presented with new-onset headaches, gait instability, and word-finding difficulty. Head CT revealed ventriculomegaly without evidence of obstruction. Brain and spine MRI showed leptomeningeal enhancements along the brainstem, dorsal aspect of the spinal cord, and cauda equina. CSF analysis was notable for increased opening pressure, pleocytosis with monocyte and lymphocyte predominance, elevated protein, and positive CSF-VDRL (1:4 titer). Although his serum VDRL was negative, he was started on penicillin-G to treat presumed neurosyphilis. PET-CT showed no FDG-avid lesions in the body. After his ventriculomegaly worsened, a second LP was performed with similar findings. Due to his ongoing hydrocephalus, three more LPs were obtained, with CSF cytopathology showing metastatic adenocarcinoma cells. Repeat CSF VDRL in all subsequent LPs had positive VDRL but in low titers ranging from 1:2 to 1:4. Immunohistochemistry was positive for several lung cancer tumor markers but negative for syphilis. A liquid biopsy for cell-free DNA also detected tumor cells in the CSF. He was subsequently started on Adagrasib.

CSF-VDRL is considered highly specific for neurosyphilis. However, in the setting of negative serologic testing for syphilis, false positivity must be considered, especially in patients with prior lung malignancy.