The Underlying Biology and Therapeutic Vulnerabilities of Leptomeningeal Metastases in Adult Solid Cancers

Abstract

Metastasis to the central nervous system occurs in approximately 20% of patients with advanced solid cancers such as lung cancer, breast cancer, and melanoma. While central nervous system metastases most commonly form in the brain parenchyma, metastatic cancer cells may also reside in the subarachnoid space surrounding the brain and spinal cord to form tumors called leptomeningeal metastases. Leptomeningeal metastasis involves cancer cells that reach the subarachnoid space and proliferate in the cerebrospinal fluid compartment within the leptomeninges, a sequela associated with a myriad of symptoms and poor prognosis. Cancer cells exposed to cerebrospinal fluid in the leptomeninges must contend with a unique microenvironment from those that establish within the brain or other organs. Leptomeningeal lesions provide a formidable clinical challenge due to their often-diffuse infiltration within the subarachnoid space. The molecular mechanisms that promote the establishment of leptomeningeal metastases have begun to be elucidated, demonstrating that it is a biological entity distinct from parenchymal brain metastases and is associated with specific molecular drivers. In this review, we outline the current state of knowledge pertaining to the diagnosis, treatment, and molecular underpinnings of leptomeningeal metastasis.

Keywords: brain metastasis; breast cancer; leptomeningeal metastases; lung cancer; melanoma; subarachnoid space.

Figure 1

Anatomy of the leptomeninges and surrounding structures. Leptomeningeal-metastatic cancer cells exist in the subarachnoid space, between the arachnoid and pia mater, deep in the dura mater and skull. Cancer cells may be adherent to the walls of the subarachnoid structures or survive in suspension in the cerebrospinal fluid (CSF). CSF is created in the choroid plexus of the lateral and fourth ventricles and flows through the ventricular system into the subarachnoid space. The subarachnoid space is separated from the brain parenchyma by the glia limitans consisting of astrocytic foot processes. The leptomeninges surrounds the entire brain and spinal cord, with notable exceptions including circumventricular organs such as the pineal gland and posterior pituitary.

Figure 2

Different appearances of leptomeningeal metastasis (LM) by histopathology in lung cancer patients. H&E stains demonstrating cancer cells (A,B) exclusively in the subarachnoid space and (C,D) in the subarachnoid space with communication of cancer cells with the brain parenchyma through local invasion. Scale bars: 1 mm.

Figure 3

Different appearances of LM by magnetic resonance imaging (MRI). (A) Patient with melanoma brain metastases. Axial (left) and coronal (right) T1 post contrast images demonstrate ependymal metastases along the lateral ventricles (arrows). There are also post-surgical changes related to the prior resection of a parietal parenchymal metastasis (asterisk). (B) Patient with lung cancer brain metastases. Axial (left) and sagittal (right) T1 post contrast images demonstrate linear, “classical”, leptomeningeal metastases along the trigeminal nerves (arrowheads) and “sugarcoating” the cerebellum (arrows). (C) Patient with lung cancer brain metastases. Axial T1 post contrast images demonstrate multiple small, superficially-located lesions, representing nodular leptomeningeal metastases