Middleton ML, Lucke-Wold B. Melanoma leptomeningeal disease: Advances in diagnosis and emerging therapeutic strategies. World J Exp Med 2026; 16(1): 117938 [DOI: 10.5493/wjem.v16.i1.117938]
Corresponding Author of This Article
Brandon Lucke-Wold, MD, PhD, Department of Neurosurgery, College of Medicine, University of Florida, 1104 Newell Drive, Unit 210, Gainesville, FL 32610, United States. brandon.lucke-wold@neurosurgery.ufl.edu
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Oncology
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Review
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Mar 20, 2026 (publication date) through Mar 20, 2026
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World Journal of Experimental Medicine
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2220-315x
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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
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Middleton ML, Lucke-Wold B. Melanoma leptomeningeal disease: Advances in diagnosis and emerging therapeutic strategies. World J Exp Med 2026; 16(1): 117938 [DOI: 10.5493/wjem.v16.i1.117938]
World J Exp Med. Mar 20, 2026; 16(1): 117938 Published online Mar 20, 2026. doi: 10.5493/wjem.v16.i1.117938
Melanoma leptomeningeal disease: Advances in diagnosis and emerging therapeutic strategies
Michael L Middleton, Brandon Lucke-Wold
Michael L Middleton, College of Medicine, University of Florida, Gainesville, FL 32610, United States
Brandon Lucke-Wold, Department of Neurosurgery, College of Medicine, University of Florida, Gainesville, FL 32610, United States
Author contributions: Middleton ML conducted the literature review and contributed to writing manuscript; Lucke-Wold B supervised the project, contributed to the conceptual framing, and revised the manuscript; and all authors have approved the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Brandon Lucke-Wold, MD, PhD, Department of Neurosurgery, College of Medicine, University of Florida, 1104 Newell Drive, Unit 210, Gainesville, FL 32610, United States. brandon.lucke-wold@neurosurgery.ufl.edu
Received: December 18, 2025 Revised: January 12, 2026 Accepted: February 3, 2026 Published online: March 20, 2026 Processing time: 86 Days and 15.1 Hours
Abstract
Melanoma leptomeningeal disease (LMD) is a rare and severe manifestation of advanced melanoma involving malignant infiltration of the leptomeninges and cerebrospinal fluid. Historically, survival was measured in weeks, but recent advances in diagnostics and therapy have begun to improve outcomes. This narrative review summarizes current evidence on the epidemiology, biology, diagnosis, and management of melanoma LMD, with emphasis on studies from the past five years. Emerging cerebrospinal fluid liquid biopsy methods, including circulating tumor cell and cell free DNA analysis, allow earlier detection, identification of actionable mutations, and real time monitoring of disease activity. Modern systemic therapies have extended median overall survival to approximately 8.4 months compared with historical outcomes of 2.9 months to 3.7 months. Immune checkpoint inhibitors and B-rapidly accelerated fibrosarcoma and mitogen-activated protein kinase targeted therapies both contribute to these improvements, and early studies of intrathecal immunotherapy show encouraging clinical activity. Additional innovations such as proton craniospinal irradiation and novel drug delivery strategies reflect an evolving treatment landscape. Continued progress will depend on dedicated clinical trials, broader inclusion of patients with LMD, and deeper understanding of the leptomeningeal immune microenvironment.
Core Tip: Melanoma leptomeningeal disease (LMD) is the most severe complication of advanced melanoma, characterized by very poor outcomes and a lack of robust evidence to inform management. This narrative review synthesizes recent advances in the understanding of LMD biology, highlights the clinical significance of evolving diagnostic strategies including neuroimaging and cerebrospinal fluid-based assays, and reviews emerging therapeutic approaches. The article contrasts LMD with parenchymal brain metastases, identifies ongoing clinical challenges, and notes key research priorities needed to improve outcomes for this historically understudied condition.
