Objective:

OBJECTIVE: To illustrate the clinical utility of cerebrospinal fluid (CSF) based liquid biopsy techniques in the diagnosis and management of leptomeningeal disease (LMD) in two distinct challenging cases.

Background:

BACKGROUND: Leptomeningeal disease (LMD) is a devastating complication of metastatic cancer, affecting approximately 15% of patients with metastatic solid tumors and associated with poor prognosis. Accurate and timely diagnosis is essential to ensure appropriate treatment and optimize quality of life. Although most cases occur in patients with known widespread disease, LMD may occasionally be the initial manifestation of malignancy, presenting significant diagnostic challenges when tissue biopsy is difficult or delayed. Liquid biopsy approaches using CSF can detect tumor cells, cell-free DNA, RNA, and protein biomarkers, providing valuable diagnostic and prognostic data.

Design/Methods:

DESIGN: Case reports of two distinct cases with respective diagnostic and treatment implications.

Results:

RESULTS: Case 1: A 56-year-old woman with no previously identified malignancy underwent MRI demonstrating leptomeningeal enhancement involving cranial nerves, brainstem and spinal cord; hydrocephalus developed with disease progression. CSF demonstrated 0.6 nucleated cells, protein 34 mg/dL, and glucose 6 mg/dL; cytology was negative. Empiric antifungal treatment was initiated. Menarini liquid biopsy ultimately demonstrated findings of solid tumor DNA with high tumor burden; subsequent biopsy confirmed histiocytic sarcoma. Case 2: A 31-year-old man with nasal rhabdosarcoma underwent brain MRI demonstrating leptomeningeal disease and hydrocephalus. CSF demonstrated 2.8 nucleated cells, and normal glucose and protein; cytology/flow cytometry showed very rare, atypical cells. Liquid biopsy/ctDNA testing confirmed leptomeningeal spread and additionally identified mutations that allowed for expedited selection of targeted treatment noting setting of uncommon tumor.

Conclusions:

CONCLUSION: These cases demonstrate how CSF liquid biopsy is a promising adjunct in the diagnosis and management of leptomeningeal disease, particularly when cytology/flow cytometry is non-diagnostic, conventional tissue diagnosis is not readily feasible, and/or rapid molecular insights are required.