Leptomeningeal Spread in Glioblastoma: Diagnostic and Therapeutic Challenges

Abstract

Background: Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. Leptomeningeal spread (LMS) is a severe complication of GBM, raising diagnostic and therapeutic challenges in clinical routine.

Methods: We performed a review of the literature focused on LMS in GBM. MEDLINE and EMBASE databases were queried from 1989 to 2019 for articles describing diagnosis and therapeutic options in GBM LMS, as well as risk factors and pathogenic mechanisms.

Results: We retrieved 155 articles, including retrospective series, case reports, and early phase clinical trials, as well as preclinical studies. These articles confirmed that LMS in GBM remains (a) a diagnostic challenge with cytological proof of LMS obtained in only 35% of cases and (b) a therapeutic challenge with a median overall survival below 2 months with best supportive care alone. For patients faced with suggestive clinical symptoms, whole neuroaxis magnetic resonance imaging and cerebrospinal fluid analysis are both recommended. Liquid biopsies are under investigation and may help prompt a reliable diagnosis. Based on the literature, a multimodal and personalized therapeutic approach of LMS, including surgery, radiotherapy, systemic cytotoxic chemotherapy, and intrathecal chemotherapies, may provide benefits to selected patients. Interestingly, molecular targeted therapies appear promising in case of actionable molecular target and should be considered.

Conclusion: As the prognosis of glioblastoma is improving over time, LMS becomes a more common complication. Our review highlights the need for translational studies and clinical trials dedicated to this challenging condition in order to improve diagnostic and therapeutic strategies.

Implications for practice: This review summarizes the diagnostic tools and applied treatments for leptomeningeal spread, a complication of glioblastoma, as well as their outcomes. The importance of exhaustive molecular testing for molecular targeted therapies is discussed. New diagnostic and therapeutic strategies are outlined, and the need for translational studies and clinical trials dedicated to this challenging condition is highlighted.

Keywords: Diagnostic; Glioblastoma; Leptomeningeal spread; Treatment.

Figure 1

Literature research flow chart showing the selection of publications used in the review. Abbreviation: LMS, leptomeningeal spread.

Figure 2

Leptomeningeal spread (LMS) in glioblastoma: routes of migration and spatial distribution of spinal LMS. (A): Routes of migration of glioblastoma cells from initial tumor site to meningeal spaces. (1, 2): Migration of glioblastoma (GBM) cells from the initial tumor site along brain vessels to subpial and subarachnoid spaces. (3): GBM cells circulating via the cerebrospinal fluid. (B): Distribution of leptomeningeal and spinal dissemination of intracranial glioblastoma.

Figure 3

Nodular leptomeningeal spread in glioblastoma. (A, B): Subependymal. (C, D): Spinal. Blue arrow indicates initial location; yellow arrow indicates nodular leptomeningeal spread.

Figure 4

Linear (diffuse) leptomeningeal spread in glioblastoma.

Figure 5

Mixed leptomeningeal spread in glioblastoma. (A, B): Subependymal. (C): Spinal. Yellow arrows indicate nodular aspects; red arrows indicate linear aspects.

Figure 6

Cytopathological aspects of leptomeningeal spread in glioblastoma. (A): Cerebrospinal fluid obtained from lumbar puncture was studied by cytocentrifugation and May‐Grünwald‐Giemsa staining. Microscopic examination showed large tumor cells with marked atypia (high nucleocytoplasmic ratio, irregular nuclear borders, prominent nucleoli, basophilic cytoplasm). (B): GFAP immunostaining (brown signal) showed cytoplasmic positivity confirming the glial lineage of the tumor cells.

Figure 7

Proposed algorithm for management leptomeningeal spread in glioblastoma. Abbreviations: CSF, cerebrospinal fluid; ECOG, Eastern Cooperative Oncology Group performance status; KPS, Karnofsky performance status; LMD, leptomeningeal disease; LMS, leptomeningeal spread; MRI, magnetic resonance imaging.