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Leptomeningeal Disease (LMD) in Patients with Melanoma Metastases
Mariam Lotfy Khaled1,2, Ahmad A Tarhini3, Peter A Forsyth4
1Metabolism and Physiology Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Abstract:
Leptomeningeal disease (LMD) is a devastating complication caused by seeding malignant cells to the cerebrospinal fluid (CSF) and the leptomeningeal membrane. LMD is diagnosed in 5-15% of patients with systemic malignancy. Management of LMD is challenging due to the biological and metabolic tumor microenvironment of LMD being largely unknown. Patients with LMD can present with a wide variety of signs and/or symptoms that could be multifocal and include headache, nausea, vomiting, diplopia, and weakness, among others. The median survival time for patients with LMD is measured in weeks and up to 3-6 months with aggressive management, and death usually occurs due to progressive neurologic dysfunction. In melanoma, LMD is associated with a suppressive immune microenvironment characterized by a high number of apoptotic and exhausted CD4+ T-cells, myeloid-derived suppressor cells, and a low number of CD8+ T-cells. Proteomics analysis revealed enrichment of complement cascade, which may disrupt the blood-CSF barrier. Clinical management of melanoma LMD consists primarily of radiation therapy, BRAF/MEK inhibitors as targeted therapy, and immunotherapy with anti-PD-1, anti-CTLA-4, and anti-LAG-3 immune checkpoint inhibitors. This review summarizes the biology and anatomic features of melanoma LMD, as well as the current therapeutic approaches.
Insights
Leptomeningeal disease (LMD) in melanoma patients presents a significant challenge due to an unknown tumor microenvironment. Understanding LMD biology and current treatments is crucial for improving patient outcomes.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Immunology
Background:
- Leptomeningeal disease (LMD) affects 5-15% of cancer patients, complicating treatment.
- LMD presents with diverse neurological symptoms and has a poor prognosis, often leading to death from neurological decline.
- The tumor microenvironment in LMD is poorly understood, hindering effective management.
Purpose of the Study:
- To review the biology and anatomical features of melanoma LMD.
- To summarize current therapeutic strategies for melanoma LMD.
- To highlight the challenges in managing LMD.
Main Methods:
- Literature review of melanoma LMD.
- Analysis of proteomics data revealing complement cascade enrichment.
- Summary of clinical management approaches.
Main Results:
- Melanoma LMD exhibits a suppressive immune microenvironment with exhausted T-cells and myeloid-derived suppressor cells.
- Proteomics identified complement cascade activation potentially disrupting the blood-cerebrospinal fluid barrier.
- Current treatments include radiation, targeted therapy (BRAF/MEK inhibitors), and immunotherapy (immune checkpoint inhibitors).
Conclusions:
- Melanoma LMD is characterized by a unique immune microenvironment and potential disruption of the blood-CSF barrier.
- Effective management requires a multimodal approach combining radiation, targeted therapy, and immunotherapy.
- Further research into the LMD microenvironment is needed to develop novel therapeutic strategies.
