Review

Leptomeningeal Metastasis: A Review of the Pathophysiology,

Diagnostic Methodology, and Therapeutic Landscape
Andrew Nguyen 1,† , Alexander Nguyen 1,† , Oluwaferanmi T. Dada 1 , Persis D. Desai 1 , Jacob C. Ricci 1 ,
Nikhil B. Godbole 2 , Kevin Pierre 3 and Brandon Lucke-Wold 4, *

1 College of Medicine, University of Florida, Gainesville, FL 32610, USA

2 School of Medicine, Tulane University, New Orleans, LA 70112, USA
3 Department of Radiology, University of Florida, Gainesville, FL 32610, USA
4 Department of Neurosurgery, University of Florida, Gainesville, FL 32610, USA
* Correspondence: brandon.lucke-wold@neurosurgery.ufl.edu
† These authors contributed equally to this work.

Abstract: The present review aimed to establish an understanding of the pathophysiology of lep-
tomeningeal disease as it relates to late-stage development among different cancer types. For our
purposes, the focused metastatic malignancies include breast cancer, lung cancer, melanoma, primary
central nervous system tumors, and hematologic cancers (lymphoma, leukemia, and multiple myeloma).
Of note, our discussion was limited to cancer-specific leptomeningeal metastases secondary to the
aforementioned primary cancers. LMD mechanisms secondary to non-cancerous pathologies, such as
infection or inflammation of the leptomeningeal layer, were excluded from our scope of review. Further-
more, we intended to characterize general leptomeningeal disease, including the specific anatomical
infiltration process/area, CSF dissemination, manifesting clinical symptoms in patients afflicted with
the disease, detection mechanisms, imaging modalities, and treatment therapies (both preclinical and
clinical). Of these parameters, leptomeningeal disease across different primary cancers shares several
features. Pathophysiology regarding the development of CNS involvement within the mentioned cancer
subtypes is similar in nature and progression of disease. Consequently, detection of leptomeningeal
disease, regardless of cancer type, employs several of the same techniques. Cerebrospinal fluid analysis
in combination with varied imaging (CT, MRI, and PET-CT) has been noted in the current literature
Citation: Nguyen, A.; Nguyen, A.;
as the gold standard in the diagnosis of leptomeningeal metastasis. Treatment options for the disease
Dada, O.T.; Desai, P.D.; Ricci, J.C.;
Godbole, N.B.; Pierre, K.;
are both varied and currently in development, given the rarity of these cases. Our review details
Lucke-Wold, B. Leptomeningeal the differences in leptomeningeal disease as they pertain through the lens of several different cancer
Metastasis: A Review of the subtypes in an effort to highlight the current state of targeted therapy, the potential shortcomings in
Pathophysiology, Diagnostic treatment, and the direction of preclinical and clinical treatments in the future. As there is a lack of
Methodology, and Therapeutic comprehensive reviews that seek to characterize leptomeningeal metastasis from various solid and
Landscape. Curr. Oncol. 2023, 30, hematologic cancers altogether, the authors intended to highlight not only the overlapping mechanisms
5906–5931. https://doi.org/10.3390/ but also the distinct patterning of disease detection and progression as a means to uniquely treat each
curroncol30060442 metastasis type. The scarcity of LMD cases poses a barrier to more robust evaluations of this pathology.
Received: 7 May 2023 However, as treatments for primary cancers have improved over time, so has the incidence of LMD. The
Revised: 14 June 2023 increase in diagnosed cases only represents a small fraction of LMD-afflicted patients. More often than
Accepted: 16 June 2023 not, LMD is determined upon autopsy. The motivation behind this review stems from the increased
Published: 19 June 2023 capacity to study LMD in spite of scarcity or poor patient prognosis. In vitro analysis of leptomeningeal
cancer cells has allowed researchers to approach this disease at the level of cancer subtypes and markers.
We ultimately hope to facilitate the clinical translation of LMD research through our discourse.

Copyright: © 2023 by the authors.

Keywords: leptomeningeal disease; metastases; central nervous system; CNS tumor
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
1. Introduction: The Pathophysiology of Leptomeningeal Disease
creativecommons.org/licenses/by/ Leptomeningeal disease (LMD) is commonly characterized as the metastatic involve-
4.0/). ment of various meningeal regions—the arachnoid mater, subarachnoid space, and pia

Curr. Oncol. 2023, 30, 5906–5931. https://doi.org/10.3390/curroncol30060442 https://www.mdpi.com/journal/curroncol

Curr. Oncol. 2023, 30 5907

mater—defined as the leptomeningeal layer. Although LMD can stem from non-cancerous
pathologies, such as multiple sclerosis (MS) or meningitis with subsequent inflammation
and infection, respectively, this review focused specifically on leptomeningeal metastasis
secondary to a neoplasm or carcinomatosis. Prevalence exists in 1–8% of all cancer pa-
tients, with a recorded incidence of 110,000 cases in the US annually [1]. Furthermore, the
prevailing sites of origin include breast and lung cancer, melanoma, and lastly, primary
central nervous system (CNS) cancers [1]. Additionally, hematologic origins, namely non-
Hodgkin’s lymphoma (NHL), acute lymphoblastic leukemia (ALL), and multiple myeloma,
are seldom negligible in occurrence [2]. Several mechanisms for the general onset of LMD
have been purported: (1) direct invasion via surrounding structures, such as the dura mater,
bone, or nerves; (2) hematogenous spread often by way of venous vasculature; and, lastly,
(3) entry of the fenestrated pores of the choroid plexus typically permitting solute trans-
port [1,3]. Within LMD-related cerebrospinal fluid (CSF), the presence of increased levels
of complement component three protein (C3) has been observed. Postulations describe the
role of C3 in its ability to interact with choroid plexus C3a receptors, thereby increasing the
endothelial permeability of the normally intact barrier [4].
Clinically, the presentation of LMD includes non-specific, generalized neurological
symptoms, such as headaches, confusion, seizures, and radiculopathy, among others.
Though this substantially shifts the weight of efficacy to other modes of diagnosis, more
refined schemas for focused diagnosis have been formally developed. For example, within
cerebral localizations, symptoms may manifest as headache and confusion, while cranial
nerve (CN) deficits may be attributed to involvement of the posterior fossa; the anatomical
afflictions and their corresponding presentations are described more extensively in recent
literature [3]. Regarding prognosis, the National Comprehensive Cancer Network (NCNN)
has established technical criteria for stratification of prognosis [5]. Karnofsky Performance
Scale (KPS) values < 60, systematic neurological presentation, and encephalopathy have
all been associated with a higher risk of disease progression. Additionally, hematologic
origins have displayed seemingly better outcomes [6]. To date, the clinical repertoire for
guiding differential diagnoses has been through obtaining medical history and physical
examination. It is important to note the overlap between COVID-19 neurological symptoms
and findings with leptomeningeal metastasis. The two pathologies share both molecular
and structural shifts. Namely, COVID-19 patients have been shown to present with CSF
positive for LMD inflammatory cytokines and MRI involvement within LMD regions of
interest. Similarities are also found in other disorders, such as Sturge-Weber syndrome
(SWS), due to the presence of leptomeningeal angiomatosis. Overall, the median time from
diagnosis of primary cancer to LMD has ranged from 1.2–2 years for solid tumors and
11 months for hematologic cancers [3].
On the matter of modality-based diagnosis, the gold standard comprises two modal-
ities in the form of imaging and cytological analyses. T1-weighted magnetic resonance
imaging (MRI) with gadolinium contrast is the imaging tool of choice. The observational
patterns to hearken to include various morphologic enhancements of the cranial nerve, or
linear/curvilinear enhancements, and nodular aberrancies [2,7]. These are often noted in
select areas, such as the cerebral convexities, basal cisterns, and ventricular ependyma [4].
Figure 1 depicts an MRI scan of leptomeningeal involvement following breast cancer metas-
tases. Within the spine, particularly in the cauda equina region, similar observations should
raise suspicion for LMD [4]. Preliminary MRI is becoming an increasingly routine measure
for early brain metastasis. As such, several structure densities along the brainstem, cranial
nerves, meninges, and ventricles have been correlated with leptomeningeal metastasis.
Of note, some findings, such as increased ventricle MRI density, can be a consequence of
LMD-associated disorders, in this case hydrocephalus. Since negative MRI findings are not
exclusionary, the second modality, CSF cytology, is an essential layer in the diagnosis of this
pathology. Conventional cytology hinges on the presence of malignant cells, irrespective of
their primary origin, as determined by a cytopathologist. However, cancer specific markers
may aid in the determination of the origin, such as the presence of VEGF. In general, the
Curr. Oncol. 2023, 30 5908

sensitivity and specificity of LMD diagnosis following CSF cytology range from 50–60%
and 75–80%, respectively, upon first and second aspirations of CSF [1,3]. Therefore, it is
highly encouraged to conduct a second analysis of the CSF when possible, in order to
increase the diagnostic capacity for LMD. As a soft requirement, a minimum of 10 CSF
mL should be collected for sufficient analysis, with some studies reporting a minimum of
5–10 mL [1,3]. Additionally, it is recommended that the suspected region of affliction (based
on several parameters, such as clinical presentation and imaging) be the area of aspiration;
in cases where this is not feasible, the lumbar or cisternal regions should be considered as
immediate alternatives [1]. The select biomarkers that are measured to supplement ruling
in LMD include pleocytosis, hypoglycorrhachia, and hyperproteinorrachia (elevated CSF
protein levels). These findings have been observed with a sensitivity of 50–70% [8]. More
novel forms of investigation have arisen in the form of tumor-specific antigens, such as
carcinoembryonic antigen (CEA) and alpha-fetoprotein. The latest of these endeavors has
manifested itself by relying on cell-free DNA as a source of direction [3]. The sensitivity of
this latter technique has been nascently explored, though its sensitivity has been reported
at 94% with a specificity of 100% [9]. Indeed, in a recent meta-analysis of 668 patients with
circulating tumor cells (CTC) and cell-free tumor DNA, sensitivities and specificities were
reported at 87.0% and 97.9% (sensitivity, respectively) and 93.8% and 89.0% (specificity,
respectively). This has been more robustly assessed in particular cancer-specific LMDs,
such as breast cancer [10]. This includes optimization of isolating and purifying circulating
tumor-specific DNA and subsequently identifying targetable mutations. Abnormal MRI
and CSF findings, as previously mentioned, in the presence of generalized neurological
symptoms can be cause for LMD suspicion.
Currently, treatment for LMD secondary to metastasis offers conventional cancer
treatment in the forms of surgery, radiotherapy, and chemotherapy. Surgical intervention
primarily involves the installation of interventricular delivery devices (i.e., the Ommaya
reservoir) or management of LMD complications, such as hydrocephalus and address-
ing excessive intracranial pressure (ICP); this entails a ventriculoperitoneal shunt (VPS)-
dependent manner of draining excess CSF [11]. Radiation is typically indicated for LMD
with the sole aim of palliation due to the late onset of diagnosis, particularly in the form
of multiple brain metastases. This is implemented in the form of whole brain radiation
therapy (WBRT) for cranial afflictions, with spinal localization utilizing traditional frac-
tionated radiation. Radiation involvement is typically forgone lest there be symptomatic
involvement or bulky disease [5]. Recent explorations have begun to assess the efficacy
of more invasive measures, namely, craniospinal irradiation (CSI). Its adequacy has been
particularly salient in cancers of hematologic origin, encouraging timely invitations for
extrapolated interest in solid cancers [12]. Dosing ranges have been reported at 20 to 40
Gy in 5 to 20 fractions, marking minimum and maximum cumulative doses of 400 Gy and
800 Gy, respectively [11].
Immunotherapy is delivered based on either the intention of systemic engagement or
focused, targeted therapies. Systemic immunotherapy, widely studied across various can-
cers and metastatic diseases, includes immune checkpoint inhibitors (ICIs) to pragmatically
modulate the endogenous immune system. Currently, high-level evidence in the form of
randomized controlled trials (RCTs) assessing systemic immunotherapies in LMDs remains
scarce. The dearth is occupied by the limited validity of various case reports, with a single
RCT displaying limited potential for the four included LMD patients [13]. The proceeding
sections will discuss primary cancer-specific therapeutics, with a major focus on targeted
immunotherapies [14–16].
Though the overarching mechanisms for the pathophysiology of LMD have been
discussed, it is well acknowledged that the mode of origin precluding the metastases
carries significant implications for engaging this disease. This manifests in the form of
diverse biomarkers, treatments, and epidemiologic profiles. Such variation may influence
the capacity and manner of treatment for the particular form of LMD. Therefore, the aim of
this review is to coalesce the available literature on LMD across the various primary origins,
Curr. Oncol. 2023, 30 5909

particularly the most prevalent forms. Furthermore, it will cohesively synthesize the current
treatments, both preclinical and clinical, while highlighting similarities and differences.

Figure 1. Bilateral cerebellar folia hyperenhancement, more prominent on the right, was observed in
the post-contrast T1-weighted Turbo Spin Echo (TSE) sequence (A); the T1-weighted Multi-Planar
Reconstruction (MPR) sequence (B); and the T2-weighted Turbo Inversion Recovery Magnitude Fat
Suppressed (TIRM-FS) sequence (C).

2. Breast Cancer
Breast cancer remains one of the leading cancer types by diagnosis, and cases have
been steadily rising over the past decades [17]. While meningeal carcinomatosis (MC)
is a rare metastatic outcome occurring in roughly 1–5% of solid tumors, primary breast
tumors, along with lung tumors and melanoma, make up the most common origin sites [18].
Among studies of patients with leptomeningeal breast cancer metastasis (LBM), the average
age of breast cancer diagnosis is often between 50 and 60 [18–23]. Once diagnosed, the
average time to develop LBM is less than 10 years [19,23]. Unfortunately, survival after
leptomeningeal metastasis remains poor. Over multiple reviews and meta-analyses, the
average survival time ranges from 16 weeks to 2 years [18–20,24–27].
Invasive breast cancer can be broken down into two common types: ductal and lobular
carcinoma. These can be further broken down into four subtypes: luminal A, luminal
B, HER2, and triple-negative cancer [28]. Luminal A cancers are either estrogen receptor
(ER) or progesterone receptor (PR) positive but human epidermal growth factor receptor 2
(HER2) negative. Luminal B cancers are ER-positive, PR-positive or negative, and HER2
negative. They are characterized by levels of Ki67 expression over 20%, equating to faster
growth relative to luminal A tumors. HER2 cancers are HER2 positive and ER/PR negative.
These tumors have been the focus of research for many years due to their faster growth than
luminal tumors and poorer prognosis. However, since the introduction of therapies that
specifically target the HER2 protein, overall survival has improved. Finally, triple-negative
breast cancer is ER/PR/HER2-negative and is notorious for presenting in later stages. It is
characterized by its aggressiveness and propensity for relapse [28].
In relation to the pathogenicity of LBM, there has been a heavy focus on the role
HER2 plays, though the overall pathogenesis remains to be elucidated. HER2 is similar
to the epidermal growth factor receptor (EGFR) and is a transmembrane protein that has
tyrosine kinase activity once activated by interactions with HER3 or EGFR [29]. Multiple
studies have implicated these interactions in the development of MC. Among these, it has
been shown that the dimerization of HER2 and HER3, as well as levels of Src, an enzyme
involved in the HER2-HER3 dimerization process, lead to increased extravasation and
increased blood-brain barrier (BBB) infiltration [30,31]. Interestingly, HER2 status does not
determine the possibility of MC development, as studies have shown that around 20% of
CNS metastases from HER2- breast primary tumors show cells that are HER2+ [32].
Curr. Oncol. 2023, 30 5910

Given that MC is a rare complication, it is often observed later in the disease course
in patients who have already developed metastatic lesions. It has been purported that
established brain metastases carry an increased risk of developing MC [33,34]. Other risk
factors include age at diagnosis and metastasis at other extracranial sites [35]. One study
has shown that surgical resection of brain metastases increases the risk of developing
MC [33]. In patients who develop MC without other CNS lesions, studies have shown that
there is significantly better overall survival as compared to those patients who develop MC
with brain metastases as well as patients with brain metastases alone [20].
As MC has a poor prognosis, it is imperative to diagnose it early and provide the
patient with the best possible opportunity to respond to treatment and prolong their life.
Unfortunately, the gold standard for diagnosis of MC is MRI and CSF cytology, which
carry a low sensitivity in diagnosing MC in its early stages [36–38]. As such, there has
been a push to develop more sophisticated diagnostic tests to detect MC. One method has
utilized CellSearch cell capture technology to detect circulating tumor cells in the CSF of
patients with suspected MC (Figure 2) [39]. Though their sample size was small, they noted
the ability of this technology to detect circulating tumor cells in CSF and mentioned one
patient with negative CSF cytology but positive circulating tumor cells who subsequently
developed positive cytology [39]. A subsequent study described a method that utilized
next-generation sequencing and fast aneuploidy screening test sequencing to determine
the presence of tumor-derived DNA in the CSF of patients with MC. They found that the
method was successful in 93% of samples, and MC was diagnosed in 75% of samples in
which aneuploidy was detected by this method. Notably, a third (8/24) of samples in
which aneuploidy was detected were concurrently diagnosed with MC or developed it
soon after this study was conducted [40]. Finally, a study published in 2022 assessed the
feasibility of using ultra-low pass whole genome sequencing to detect tumor-derived DNA
(ctDNA) in CSF. The benefit of this method is that it does not require the sequencing of a
primary tumor. While they found ctDNA in all patients with diagnosed MC, they showed
that greater suppression of ctDNA levels during treatment was associated with longer
overall survival, and an increase in ctDNA levels was detectable 12 weeks prior to clinical
progression of the disease [41]. With respect to imaging detection, Pan et al. detailed a case
report in which an LBM patient demonstrated a “hot cross bun” (HCB) shape indicative of
multi-region brain deterioration. Although these T-2 MRI hyperintensities overlap with
other neurodegenerative diseases, the patterns may be a beneficial tool in monitoring the
status of individuals with breast cancer. Overall, there are multiple methods that show
promise for improving the ability to detect MC, but robust trials are still necessary.
Treatment strategies for MC include intrathecal chemotherapy, systemic chemotherapy,
and radiotherapy. While recent advances have shown better control of the disease, there is
still a lack of robust randomized control trials, and substantial improvements in overall
survival have yet to be shown. Given this, there has been a focus on prognostic factors
to help manage patient care. By far, the most commonly reported predictor of poor
prognosis is performance status [22,23,42,43]. However, studies have also exhibited that
negative prognostic factors include negative hormone receptor status, higher histological
tumor grades (2 and 3), and the use of more than three treatment lines [22,23,42–44].
The use of concomitant therapy has been shown to be a positive prognostic factor [44].
There have been multiple clinical trials analyzing treatment strategies for MC. Recent
Phase II trials have shown that intrathecal liposomal cytarabine combined with systemic
chemotherapy improves overall survival by roughly 3 months [45]. For patients with
HER2-positive cancers, a study has shown that intrathecal administration of trastuzumab
prevented neurological progression-free survival in 75% of patients at 10 weeks with no
significant toxicity [46]. Lastly, in patients receiving radiotherapy, a study comparing
proton and photon irradiation showed that proton irradiation was associated with longer
CNS progression-free survival and longer overall survival compared to photon therapy.
Currently, there is a clinical trial enrolling patients that is investigating the combination of
pembrolizumab and Lenvatinib for controlling MC (NCT04729348). While these studies
 Curr. Oncol. 2023, 30, 6

longer overall survival, and an increase in ctDNA levels was detecTable 12 weeks prior to
Curr. Oncol. 2023, 30 clinical progression of the disease [41]. With respect to imaging detection, Pan et al. de- 5911
tailed a case report in which an LBM patient demonstrated a “hot cross bun” (HCB) shape
indicative of multi-region brain deterioration. Although these T-2 MRI hyperintensities
overlap with other neurodegenerative diseases, the patterns may be a beneficial tool in
have shown the
monitoring promising
status of results, it should
individuals be kept
with breast in mind
cancer. that
Overall, trial
there arepopulations
multiple meth-are small
asods
it isthat
a rare
showcomplication, and larger
promise for improving thetrials
abilityare necessary
to detect to determine
MC, but robust trialsifare
effects
still are of
necessary.
statistical and clinical significance.

Figure2.2.Schematic
Figure Schematic ofof current
currentmethods
methodsforfordiagnosing
diagnosing meningeal carcinomatosis.
meningeal All methods
carcinomatosis. All methods
begin with CSF sample collection. The current gold standard is CSF cytology (1). (2) describes the
begin with CSF sample collection. The current gold standard is CSF cytology (1). (2) describes the
process of identifying tumor cells in CSF samples using CellSearch technology. (3) is the method of
process of identifying
identifying tumor
cell-free DNA cells using
(cfDNA) in CSF samples using
mFAST-SeqS. CellSearch
(4) shows technology.
the method (3) is cfDNA
of identifying the method of
identifying cell-free DNA
using ultra-low-pass whole(cfDNA) using mFAST-SeqS.
genome sequencing (ulpWGS). (4) shows the method of identifying cfDNA
using ultra-low-pass whole genome sequencing (ulpWGS).
Treatment strategies for MC include intrathecal chemotherapy, systemic chemother-
3. apy,
Lung andCancer
radiotherapy. While recent advances have shown better control of the disease,
there is still
Albeit rare,a lack of robust randomized
leptomeningeal controlmetastasis
lung cancer trials, and substantial
(LLM) canimprovements
occur, including in non-
overall survival have yet to be shown. Given this, there has been a focus on prognostic
small cell lung cancer (NSCLC), which includes adenocarcinomas, squamous cell carci-
factors to help manage patient care. By far, the most commonly reported predictor of poor
nomas, and large cell carcinoma [47]. Lung cancer is the leading cause of cancer death in
prognosis is performance status [22,23,42,43]. However, studies have also exhibited that
the United States, with approximately 57% of NSCLC patients progressing to a metastatic
negative prognostic factors include negative hormone receptor status, higher histological
state [48].
tumor The (2
grades CNSandis3),a and
common
the usesite for lung
of more thancancer metastases,
three treatment lineswith 10–20% of
[22,23,42–44]. Thepatients
with NSCLC exhibiting brain metastases (BM) at the time of diagnosis
use of concomitant therapy has been shown to be a positive prognostic factor [44]. There [49]. From the start
ofhave
intracranial involvement,
been multiple 2–12%
clinical trials of cases
analyzing exhibit strategies
treatment LMD, although
for MC.LLM Recentcan present
Phase II later
intrials
patients
have as well,that
shown even up to several
intrathecal years
liposomal following
cytarabine diagnosis
combined with [50,51].
systemicIn individuals
chemo-
40therapy
years of age or younger,
improves the incidence
overall survival by roughlyof3 lung
months cancer remains
[45]. For patientsrelatively low and rises
with HER2-pos-
itive cancers,from
significantly a study has 65
ages shown
to 84that intrathecal
[47]. The age administration of trastuzumab
of patients with a solid LMD prevented
malignancy
is consistent in multiple studies, with most reports showing patient age being in the late
50s [52,53]. Certain demographics of patients with NSCLC can be at increased risk of
intracranial dissemination as well. There is strong evidence from many studies that patients
with an advanced, local EGFR protein mutation present in an adenocarcinoma are at higher
risk of developing BM. Almost universally, studies have shown that women have a higher
frequency of EGFR mutations than men, with up to 42% of females with NSCLC exhibiting
mutations and male percentages being up to 14% [54,55]. Patient cases of anaplastic lym-
phoma kinase (ALK)-rearranged NSCLC show a similar increase in rates of BM [56]. LLM
following NSCLC has a very poor prognosis. Even with aggressive treatment and advances
Curr. Oncol. 2023, 30 5912

in therapeutic approaches, survival remains low at 3 to 11 months following diagnosis and

treatment [57]. Advantageously, LLM from NSCLC is more readily detected due to recent
improvements in imaging and treatment of NSCLC. Small-cell lung carcinoma (SCLC) may
also lead to LLM, with the incidence estimated to be 10% in patients with solid tumors [58].
The most common type of NSCLC is lung adenocarcinoma (LUAD), which occurs in
47% of cases in Western countries. After LUAD, lung squamous cell carcinoma (LUSC) is
the second most common. Tobacco smoking is the main risk factor for developing lung
cancer, with growing evidence that up to 90% of lung cancer cases are significantly caused
by active or passive smoking [59]. In addition, air pollution is responsible for approxi-
mately 5% of lung cancer-related deaths [60]. The development of NSCLC and SCLC is also
influenced by factors like age, BMI, chronic disease, diet, and alcohol consumption. LLM de-
velops through hematogenous spread, endoneurial or perineural routes, and direct seeding
through metastases in the brain or cranium [61]. As mentioned before, lung cancers have
the potential to be highly metastatic, with up to 50% of cases being metastatic at diagnosis
and a common target being the brain [62,63]. In metastasis, cancer cells engage in a cascade
consisting of local tissue invasion, intravasation into the blood, circulation, extravasation,
and colonization in the target organ. As previously noted, BMs are seen increasingly in
LUADs with EGFR mutations and ALK rearrangements. Many factors regulate tumor
cell migration, growth, and invasion, including cytokines, adhesion molecules, and gene
activity. One example was the increased level of metastasis and subsequent poor prognosis
found in LUADs that exhibited high smooth muscle actin gene (ACTA2) activity [64]. It is
important to note that there is likely no exact formula of necessary gene activity for each
lung tumor cell to reach metastasis; it is more likely that each lung tumor cell has adapted
to its circumstances and developed its own mechanism to reach a metastatic state, as the
migration of tumor cells is regulated by different genes [64].
Patients with LMD can present with a wide variety of symptoms due to different areas
of the CNS being affected. The most common presentations of LMD include headache or
back pain, nausea, vomiting, cranial nerve paralysis, walking difficulties, seizures, and
neurological defects [65]. Even so, these symptoms are mostly nonspecific and cannot alone
justify a diagnosis of LMD. Extensive clinical testing and thorough neurological evaluations
need to be made before a diagnosis can be made [65]. The EANO-ESMO guidelines
for LMD diagnosis and treatment were created in 2017 and provide specific diagnostic
criteria and neuroimaging- and cytopathology-based classifications of LM syndromes to
derive pragmatic treatment algorithms. Many details of the epidemiology, prognosis, and
therapeutics are detailed in the 2017 study. The gold standard for comprehensive LLM
patient imaging is cerebrospinal gadolinium-enhanced MRI of the brain and spine [65,66].
Classic imaging abnormalities on brain MRI are diffuse leptomeningeal enhancements
along the gyri, sulci, cortical surfaces, cranial nerves, and cerebellar folia [67]. A CSF biopsy
is a necessary follow-up to confirm the presence of LMD, with the gold standard being CSF
cytology. Epithelial cancers, such as lung cancer, express epithelial cell adhesion molecules
(EpCAMs), which can be a marker used in EpCAM-based flow cytometry, a method of
LMD diagnosis that may have a higher sensitivity and specificity than CSF cytology [65].
Recently, there have been efforts to find novel biomarkers that can point to LLM. One
2023 study shows that specific CSF exosomal microRNAs can be potential biomarkers for
NSCLC LLM, providing several examples [68].
There are currently several ongoing studies on proposed novel CNS therapies and
targets for NSCLC. CHRYSALIS is an ongoing study seeking to evaluate the use of Ami-
vantamab (an IV-administered monoclonal antibody targeting EGFR and MET mutations)
and Iazertinib (an orally administered EGFR tyrosine kinase inhibitor (TKI)) in patients
who have not received treatment and in relapsed patients [69]. MARIPOSA is a clinical
trial that seeks to compare the safety and efficacy of the combination treatment found in
CHRYSALIS to single-agent Osimertinib for EGFR-mutated NSCLC [70]. TRIDENT-1 is a
study evaluating the use of repotrectinib (a ROS-1 inhibitor/TKI in ROS-1) in ROS-1 mutant
NSCLC patients [69]. Early trials in the study show that the treatment is well tolerated [69].
Curr. Oncol. 2023, 30 5913

Treatment of LMD mostly focuses on symptom alleviation and palliation due to the
poor prognosis of the condition. Radiotherapy is one of the most common approaches to
all types of LMD management and has been widely used. Craniospinal irradiation, which
administers radiation to the entire neuroaxis, has recently been utilized with modern-day
techniques. One such technique, proton beam therapy, has been emphasized as having
a lowered risk of treatment toxicity [71]. Systemic chemotherapy in combination with
intrathecal chemotherapy remains the standard treatment for non-nodular types of LM. As
systemic chemotherapy has been reported to be an independent predictor of survival, it
is the treatment of choice for NSCLC patients with LLM [57]. A consensus has not been
reached on the standard of chemotherapy, although bevacizumab-erlotinib and pemetrexed
have been used successfully in previous clinical trials [57]. Intrathecal chemotherapy shows
a significant level of efficacy for NSCLC patients, but the optimal drug of choice, schedule,
and dosing regimen have not yet been established. Methotrexate, cytarabine, and thiotepa
remain the three most commonly administered intrathecal chemotherapy drugs, although
intrathecal methotrexate administered alone remains the most widely utilized and the most
efficacious [72]. Molecular targeted therapy should be considered when treating NSCLC
patients with LLM, as it has a history of improving clinical outcomes. Patients with EGFR
mutations may benefit from EGFR tyrosine kinase inhibitors. Gefitinib, a first-generation
EGFR inhibitor, has been shown to increase favorable outcomes among LUAD patients
with LMD when given at standard or high doses [57]. Afatinib, Osimertinib, and AZD3759
are tyrosine kinase inhibitors that have shown significant cranial and CNS penetration [57].

4. Melanoma
Melanoma has the highest association with LMD, and approximately 5% of melanoma
cases metastasize to the leptomeninges. The incidence of leptomeningeal melanoma
metastasis (LMM) is between 5–25% and can be as high as 30% [3,73]. This incidence
is undervalued because undiagnosed LMD is commonly found post-mortem [73]. In a
retrospective review by Chorti et al. (n = 52), the median time between the diagnosis
of primary melanoma and LMM was 8.5 months [74]. LMM can occur at any age, and
while the risk of melanoma increases as we age, on average, patients are diagnosed with
melanoma at the age of 65 [75]. The prognosis for patients with LMM remains grim at
17–22 weeks despite advancements in treatment [73,74,76]. There are exceptions to this
survival duration range, as exemplified by a case report from Marinova et al., demonstrat-
ing that a 43-year-old patient with BRAF-positive stage IIIa melanoma was responsive
to radiation and immunotherapy. The patient continued to survive for 2.5 years with
neurological symptoms [76]. Many patients with LMM fail to respond to treatment and
often die from severe systemic disease burden, tumor progression, and medication toxicity.
It has been theorized that the advancement of melanoma treatment has led to an increase
in the incidence of LMM because the CSF serves as a sanctuary for cancer cells given that it
is a protected environment from systemic therapy [73,76].
Melanoma is one of the most aggressive forms of skin cancer and the third most com-
mon skin cancer after basal and squamous cell carcinomas. As the name implies, melanoma
derives from the pigment-producing melanocyte basal cells of the epidermis [73,77]. This
deadly cancer can metastasize from a relatively small primary tumor of less than 1 mm
thickness and accounts for the greatest number of fatalities from skin cancer. It has a high
rate of metastases, often to brain parenchyma and CSF. Its ability to metastasize more
efficiently than other cancers arises from its superior ability to evade host defenses, genetic
variability, and similarity to angiogenic cells of the vasculature [77].
As melanoma develops, it accumulates mutations that aid in its dissemination to the
leptomeninges. These mutations include cell adhesion molecules like those found on cells
of the vascular system. This form of molecular mimicry allows metastatic melanoma cells
to resist the turbulent flow of the vasculature, extravasate from the vessel, and adhere to
other organs [77–80]. Melanoma cell adhesion molecules (MCAM/MUC18) are unique to
metastatic melanoma and not present in normal melanocytes. This molecule is associated
Curr. Oncol. 2023, 30 5914

with extravasation, and the immunotherapies targeting it have been effective in reducing
extravasation and adhesion to certain cells [77–80]. There is evidence for an association
between MUC18 and matrix metalloproteinase (MMP) activity. MMPs degrade the base-
ment membrane and allow melanoma to invade the vasculature. Other adhesion molecules
that aid in the dissemination of melanoma include L1-CAM, E-cadherin, N-cadherin, and
many more [77]. Additionally, metastatic melanoma often harbors a mutation in the BRAF
gene. This mutation causes an upregulation of the MAPK pathway, which is associated
with growth and proliferation [72].
Metastatic melanoma cells resist the turbulent flow of the vasculature and migrate
to the vessels of the arachnoid mater and pia mater [77]. Once they reach this site, the
metastatic melanoma can extravasate from the vasculature to the subarachnoid space,
where it spreads through the CSF [77–80]. Once the melanoma has extravasated, it must
establish a blood supply through angiogenesis to proliferate. It does so by expressing certain
inflammatory molecules like IL-8 and vascular endothelial growth factor A (VEGFA), which
is induced by IL-8 [77–80].
Patients with primary melanoma can be cured, but metastatic melanoma patients have
a 5-year survival rate of less than ten percent. For this reason, early diagnosis of melanoma
is vital [77]. The diagnosis of LMM can be impeded by the diverse and non-specific
presentation of headaches, pain, weakness, and neurological deterioration [73]. Similar to
other LMDs, T1-weighted magnetic resonance imaging (MRI) with gadolinium contrast
and cytology are the gold standard diagnostic tools of choice for LMM [3,73]. Cytology is
more definitive for diagnosing LMM as it has high specificity but low sensitivity [73].
Melanocytes originate from neural crest cells during development, and these cells can
develop into rare primary CNS melanomas. Primary CNS melanomas can be differentiated
from metastatic melanoma based on clinical presentation. Primary CNS melanomas usually
develop in younger patients under 50 years old and most often metastasize to systemic
organs. If a systemic focus is not found, a diagnosis of primary CNS melanoma can
be made.
Other emerging diagnostic tools include ctDNA and CellSearch® Veridex, which are
used to detect circulating tumor cells (CTC) in the blood [81,82]. ctDNA is cell-free DNA,
which is circulating DNA that arises from cells that have died. In ctDNA detection, the
presence of mutations in floating DNA, like BRAF or KRAS mutations, is quantified using
Next Generation Sequencing (NGS) or Droplet Digital PCR (ddPCR). In one study by
Ballester et al. (n = 7), the researchers found a higher correlation between ddPCR and
MRI than between CSF cytology and MRI. They also noted that NGS did not produce
correlative results with MRI [81]. Furthermore, they concluded that NGS and ddPCR
have high specificity, as they did not note any false positives. Ultimately, they concluded
that ddPCR is a better diagnostic tool than CSF cytology. In the study by Le Rhun et al.,
they found that CellSearch® Veridex could accurately detect malignant cells; however, the
sample size only included two patients. More rigorous research is required to prove the
efficacy of this modality [82].
Given the poor prognosis of LMM, the goal of treatment is palliative, with a focus on
prolonging life while maximizing comfort and avoiding toxicities from medications [3,73].
Conventional methods of therapy include radiation therapy, the placement of an Ommaya
reservoir/VP shunt to relieve hydrocephalus, and systemic therapy. The efficacy of radia-
tion therapy is still being investigated, with variable results [3,73,83]. Patients are evaluated
for responsiveness to treatment based on the Karnofsky Performance Status (KPS) scale,
which measures functional capacity [3]. If they have a score less than 60, patients are
less likely to be responsive to treatment, and it is recommended that they be spared from
aggressive interventions [84].
Clinical evidence and the development of immunotherapy for patients with LMM are
limited given the exclusion of LMM patients from many clinical trials. ICS and targeted
therapies (TT) are treatments that have not been thoroughly investigated. In the past,
Curr. Oncol. 2023, 30 5915

patients would receive whole-brain radiotherapy as a palliative measure for headaches and
intrathecal chemotherapy [14,73,74,85–87].
Patients with melanoma are identified as being BRAF + or −, which greatly impacts
their treatment options. The discovery of the BRAF mutation in half of all melanoma
cases and the creation of small-molecule BRAF kinase inhibitors like vemurafenib revo-
lutionized the treatment of melanoma. It remains unclear whether the concentration of
these drugs reaches therapeutic levels in the CSF. BRAF + patients with LMM have been
shown to be responsive to vemurafenib, dabrafenib, and trametinib; however, evidence
mostly consists of case reports, and more vigorous research is required to elucidate the
efficacy of these drugs [86–88]. Similarly, checkpoint inhibitors like ipilimumab, nivolumab,
pembrolizumab, and intrathecal interleukin-2 (IL-2) show promise in the treatment of
LMM, but the evidence is limited. Several clinical studies studying the efficacy of combined
drug interventions, including IT and checkpoint inhibitors, in the treatment of several
tumor types, including melanoma and LMM, are in progress [73,89]. Overall, patients who
received systematic treatment only had a survival rate of 3.9 months longer than those who
did not [14,90].

5. Primary Central Nervous System Tumors

Curr. Oncol. 2023, 30,Leptomeningeal
dissemination is observed in 10–20% of primary CNS tumors. 11Pe-
diatric tumors result in more frequent dissemination, with 20–30% expressing positive
CSF cytology [91]. >95% of primary nonhematologic CNS tumors with metastasis were
grade or malignant
high-grade or malignant [91]. Histopathological
[91]. Histopathological characteristics, such
characteristics, suchasashistopathological
histopathologicaltu-
mor grade and tumor angiogenesis, have been associated with leptomeningeal spread.
tumor grade and tumor angiogenesis, have been associated with leptomeningeal spread.
CSF seeding during surgery is another proposed mechanism for particular tumors. The
CSF seeding during
majoritysurgery is another
of metastatic tumors proposed mechanism
in CSF displayed for particular
cytomorphology tumors.
reminiscent The
of the pri-
majority of metastatic tumors
mary tumor [91].in CSF displayed cytomorphology reminiscent of the primary
tumor [91]. Management primarily consists of surgical management as a mainstay, often coupled
with chemoradiotherapy. These approaches generally consist of whole craniospinal irra-
Management primarily consists of surgical management as a mainstay, often coupled
diation and intrathecal chemotherapy. Radiotherapy, despite its increasing use in pediat-
with chemoradiotherapy.
ric treatment,These approaches
is still generally
associated with consist
significant of whole
long-term craniospinal
consequences and isirradia-
thus
tion and intrathecal
avoidedchemotherapy. Radiotherapy,
when possible. Long-term sequelaedespite
include its increasingdefects,
neurocognitive use inendocrine
pediatric
treatment, is stilldysfunction,
associated withdefects,
growth significant
and an long-term
increased riskconsequences and is More
of a second malignancy. thusrecently,
avoided
clinical trials have
when possible. Long-term highlighted
sequelae anti-angiogenic
include neurocognitiveinhibitors as having
defects, promisingdysfunction,
endocrine therapeutic
value [92]. Systemic anti-angiogenic treatment with bevacizumab alone and in combina-
growth defects, tion
andwith
an increased risk of a second malignancy. More recently, clinical trials
chemoradiotherapy translated into effective symptom control in five out of nine
have highlighted anti-angiogenic inhibitors
patients and increased overall as (Figure
survival having 3).promising therapeutic value [92].
Systemic anti-angiogenic treatment with bevacizumab alone and in combination with
chemoradiotherapy translated into effective symptom control in five out of nine patients
and increased overall survival (Figure 3).

Figure 3. Targeted bevacizumab therapy for leptomeningeal disease originating from the central
Figure 3. Targeted bevacizumab therapy for leptomeningeal disease originating from the central
nervous system. nervous system.

Glioblastoma (GBM) has been shown to metastasize to the leptomeninges. Known to

spread locally throughout the brain parenchyma, malignant astrocytic tumors are only
associated with leptomeningeal spread in 10–21% of cases. Demir and colleagues report
the dissemination of a pediatric GBM [93]. Pohar and colleagues describe another meta-
static GBM in a 63-year-old female [94]. Spread to the leptomeninges is found to be pri-
 Curr. Oncol. 2023, 30 5916

Glioblastoma (GBM) has been shown to metastasize to the leptomeninges. Known

to spread locally throughout the brain parenchyma, malignant astrocytic tumors are only
associated with leptomeningeal spread in 10–21% of cases. Demir and colleagues report the
dissemination of a pediatric GBM [93]. Pohar and colleagues describe another metastatic
r. Oncol. 2023, 30, GBM in a 63-year-old female [94]. Spread to the leptomeninges is found to be primarily
hematogenous or by direct extension along compact fiber pathways, such as nerves or
subependymal regions (Figure 4). In this patient, the tumor infiltrated the lateral ventricle
and spread via CSF. On histopathological examination, the tumor was found to be positive
of GBMs.
for GFAPGliomas expressing
and vimentin. StudiesIDH-1 wild-type
have linked may expression
low GFAP be associated with leptomening
with increased lep-
tomeningeal spread [95]. This may indicate that less differentiated astrocytes
spread. Histone gene mutations are another well-known predictor of leptomeningeal d are implicated
in metastasis. An important molecular marker specific to GBM is isocitrate dehydrogenase
semination in GBM. H3K27M mutations are associated with posterior fossa and midl
(IDH). According to WHO, IDH-1 and IDH-2 mutations are found in 10–15% of GBMs.
tumors and expressing
Gliomas are associated with leptomeningeal
IDH-1 wild-type may be associated disease and a poor spread.
with leptomeningeal prognosis.
His- The p
marytone
management
gene mutationsof this tumorwell-known
are another is surgical. Gross of
predictor craniotomies
leptomeningeal and gross totalinresectio
dissemination
were GBM.
performed
H3K27Minmutations
the aforementioned studies.
are associated with The
posterior standard
fossa of care
and midline tumorsgenerally
and are involv
combination adjunctive chemoradiotherapy. In general, the prognosis is poor,ofand tre
associated with leptomeningeal disease and a poor prognosis. The primary management
this tumor is surgical. Gross craniotomies and gross total resections were performed in the
mentaforementioned
is palliative. studies.
Multiple case reports have identified the leptomeningeal spread
The standard of care generally involves combination adjunctive
GBMchemoradiotherapy.
[96,97]. A systematic In general, theshowed
review prognosisaismedian
poor, andtime to spinal
treatment metastasis
is palliative. of 10 mon
Multiple
and acase
median
reportsoverall survival
have identified theof 3 months following
leptomeningeal spread of GBMspinal metastasis.
[96,97]. A systematicPalliative
review lamin
showed a median time to spinal metastasis of 10 months and a median
tomies have also been performed to ameliorate symptoms. Neither palliative laminectom overall survival of
3 months following spinal metastasis. Palliative laminectomies have also been performed
CT, nor RT have demonstrated therapeutic advantage. Interestingly, surgery may hav
to ameliorate symptoms. Neither palliative laminectomy, CT, nor RT have demonstrated
therapeutic advantage,
therapeutic advantage.as those whosurgery
Interestingly, underwent
may have only a biopsyadvantage,
a therapeutic had a shorter time to d
as those
velopwho
spinal metastasis
underwent only a[98].
biopsy had a shorter time to develop spinal metastasis [98].

FigureFigure
4. T1-weighted
4. T1-weightedcontrast-enhanced
contrast-enhanced MRI MRI demonstrated
demonstrated a large
a large B-cell B-cell centered
lymphoma lymphoma in thecentered
the subependymal regions of the lateral ventricles.
subependymal regions of the lateral ventricles.

Germ Germ
cellcell tumorsalso
tumors alsoaccount
account for
fora share of leptomeningeal
a share metastases.
of leptomeningeal Intracranial
metastases. Intracran
germinomas account for 3% of neoplasms in children aged 0–19 in North America and
germinomas account for 3% of neoplasms in children aged 0–19 in North America and
of intracranial neoplasms in Asia. Malignant germinomas spread in a periventricular p
tern through infiltration of the subependymal lining. Classical biomarkers include an e
vated alpha-fetoprotein and a low-to-normal beta human chorionic gonadotropin. Due
the prevalence of variants, these biomarkers can vary, making diagnosis challenging. H
Curr. Oncol. 2023, 30 5917

15% of intracranial neoplasms in Asia. Malignant germinomas spread in a periventricular

pattern through infiltration of the subependymal lining. Classical biomarkers include an
elevated alpha-fetoprotein and a low-to-normal beta human chorionic gonadotropin. Due
to the prevalence of variants, these biomarkers can vary, making diagnosis challenging.
Historically, these have been treated with craniospinal irradiation. Due to high levels
of toxicity, this approach is being replaced by targeted local and ventricular approaches.
Preradiation chemotherapy is also being utilized to allow for lower doses of radiation to
be administered.
Medulloblastomas and neuroendocrine tumors are also associated with drop metas-
tasis. In a case study on medulloblastoma, the patient was positive for synaptophysin
and chromogranin A and negative for GFAP, EMA, and CD20 [99]. Genetic analyses have
identified key genes involved in metastasis. Overexpression of Arnt and Gdi2 genes in
sonic hedgehog-induced medulloblastomas was found to increase migration, invasive-
ness, and anchorage-independent growth, increasing the metastatic compliance of cells.
MiRNA-21 and ID3 have also been implicated in metastasis, and their suppression has
been associated with improved outcomes [100–102]. One survival analysis found late-drop
metastasis to be a negative prognostic factor, revealing a significant drop in overall survival.
In this population, although palliative, treatment of leptomeningeal metastasis was found
to stabilize and protect the brain from further neurologic deterioration. Patients in high-risk
subgroups received adjuvant craniospinal radiation and intrathecal chemotherapy, as well
as stereotactic radiosurgery. Detection of this metastasis was also found to be a significant
challenge, with advanced neuroimaging needed to diagnose it [103]. Pinealoblastoma is
another rare neuroendocrine neoplasm with documented spinal drop metastasis. These
occur in the pineal region and contain highly anaplastic and necrotic features, as well as
rosette structures. Additionally, they are positive for neural markers, such as synaptophysin
and negative for glial markers, such as GFAP, pancytokeratin (PanCK), and epithelial mem-
brane antigen (EMA). Initially, pineoblastomas are managed with maximal tumor resection
coupled with adjuvant chemoradiotherapy. The presence of leptomeningeal metastasis is
an indicator of a poor prognosis. Pinealoblastomas are theorized to hematogenously seed
in the spinal fluid. Inactivation of Rb and P53 has been associated with leptomeningeal
metastasis of pinealoblastoma. Surgical management of metastatic disease is a mainstay
for this pathology, followed by adjuvant chemoradiotherapy [104]. Another case study
identified a primary neuroendocrine tumor of the pineal gland with drop metastasis to the
spine [105]. Choroid plexus carcinoma is a rare intraventricular neoplasm affecting children.
The tumor’s site of origin, the choroid plexus epithelium, makes it prone to seeding the
neuraxis through cerebrospinal fluid. Maximal surgical resection coupled with adjuvant
chemoradiotherapy is the current preferred treatment regimen. Radiotherapy, namely
craniospinal irradiation and whole brain radiotherapy, has been identified as providing
better clinical outcomes than chemotherapy. Despite this, chemotherapeutic approaches
are under investigation, although an optimal approach is currently unknown.
Embryonal tumors are highly malignant neoplasms primarily affecting young children
with a tendency to metastasize along the neuraxis. Embryonal tumors with abundant
neuropil and true rosettes (ETANTR) are a set of embryonal tumors with a poor prognosis.
Unique molecular features include miRNA cluster C19MC amplification and LIN28A
positivity. These features are associated with aggressive tumor growth, tumorigenesis, and
poor survival. Optimal treatment for this tumor involves maximally safe surgical resection
and adjuvant risk-adapted chemoradiotherapy. Proton therapy is a promising frontier in
radiotherapy that can limit damage to the heart, lungs, and bowel in patients with ETANTR.
Atypical teratoid/rhabdoid tumor (AT/RT), a rare embryonal CNS neoplasm, is known
to metastasize to the leptomeninges. Tumor dissemination is reported in 24% of patients
at the time of diagnosis and in another 35% within 3 years. Metastatic AT/RTs appear as
large cells with rhabdoid morphology. AT/RTs are characteristically INI1-negative due to a
SMARCB1 gene deletion. The standard of care for metastatic disease favors chemotherapy
to avoid the toxic effects of radiotherapy. Despite this, some studies suggest that aggressive
 Curr. Oncol. 2023, 30 5918

early craniospinal irradiation in children > 3 years of age is imperative to prevent further
metastasis. Intrathecal chemotherapy has been explored as a means of treating metastatic
AT/RT as an alternative to radiation. In these trials, various combinations of methotrexate
and cytarabine have demonstrated success.
Spinal seeding metastasis has also been observed in oligodendrogliomas. These
tumors are associated with recurrence and lethal outcomes. Drop metastasis is seen in 1–2%
of all cases. This phenomenon is depicted in Figure 5. There is no information on how
this occurs, and blood and lymphatic metastasis are proposed mechanisms. The time to
metastasis has been reported to be anywhere between 3 months and 6 years. Metastasis
has been associated with a higher histopathological grade, although seeding can occur
without malignant transformation. Following decompression surgery, this patient was
managed with chemoradiotherapy [106]. Another case report describes a similar patient
with spinal metastasis following resection of a low-grade frontal oligodendroglioma. In this
case, surgical resection allowed for an overall survival of 1 year after the initial diagnosis.
Spinal metastasis was found to occur years after resection of the primary tumor in this case,
and spinal seeding was demonstrated to be a negative event indicating short survival [107].
Primary CNS melanoma has also been associated with metastasis. Melanoblasts are of
neural crest origin and migrate to the skin, uvea, mucous membranes, and leptomeninges
during development. Leptomeningeal spread may be linked to its histogenetic origin [108].
Somatic mutations most commonly occur at the Q209 and R183 residues of GNAQ and
r. Oncol. 2023, 30, induce tumorigenesis through upregulation of the MAP kinase pathway. Primary CNS
melanoma either invades the meninges diffusely or presents as nodular intraparenchymal
lesions. The ease of meningeal invasion may be because it is highly vascularized. The
prognosis for metastatic disease is very poor. As such, the treatment approach is primarily
Spinalpalliative, not curative.
metastasis was foundTreatment included
to occur years radiotherapy and intra-CSF
after resection chemotherapy.
of the primary tumor in t
Survival time in this case was 13 months after diagnosis. Another case report identified a
case, primary
and spinal seeding was demonstrated to be a negative event indicating short survi
temporal lobe malignant melanoma with extracranial metastasis to the spinal cord
[107].and lungs [109].

FigureFigure
5. T1-weighted contrast-enhanced
5. T1-weighted MRI
contrast-enhanced MRI demonstrating
demonstrating drop metastases
drop metastases at T6 (A),at
T3,T6 (A),
and T9 T3, and
(B) in(B)
a patient who
in a patient previously
who previously underwent a resection
underwent a resection for
for an an ependymoma.
ependymoma.

Meningioma has also been associated with leptomeningeal spread. A case report
Primary CNS melanoma has also been associated with metastasis. Melanoblasts a
described a 27-year-old female with rhabdoid meningioma. Histological examination
of neural crest
revealed origin and
rhabdoid andpapillary
migratemeningiomas,
to the skin, uvea, mucous
which were membranes,
vimentin and leptomen
and S-100 positive
ges during development. Leptomeningeal spread may be linked to its histogenetic orig
[108]. Somatic mutations most commonly occur at the Q209 and R183 residues of GNA
and induce tumorigenesis through upregulation of the MAP kinase pathway. Prima
CNS melanoma either invades the meninges diffusely or presents as nodular intrapare
Curr. Oncol. 2023, 30 5919

with EMA expression. The patient was managed with a subtotal resection followed by
radiotherapy. The patient died 3 months after symptom onset. It is believed the combination
of anaplasia, high mitotic index, and loss of cohesion between neoplastic cells led to diffuse
leptomeningeal metastasis [110].

6. Hematologic Cancers
Although hematologic malignancies range in subtypes, they refer to cancers afflicting
the blood, bone marrow, and lymph nodes [111]. This grouping includes cancers, such
as lymphoma, leukemia, and multiple myeloma. Lymphomas are categorized as either
Hodgkin’s lymphoma or NHL [112]. Hodgkin’s lymphoma (10% of lymphoma cases)
is marked by the presence of Reed-Sternberg cells and CD15 and CD30 staining, along
with distinct clinical characteristics, whereas NHL (90% of lymphoma cases) lacks these
specific features [113]. Rather, NHL is characterized by CD19- and CD20-positive mark-
ers [114]. Additionally, Hodgkin’s lymphoma and NHL can further be subdivided into
over 90 different subtypes [115]. Leukemias consist of cancer subtypes, such as acute
myeloid leukemia, chronic myelogenous leukemia (CML), ALL, and chronic lymphoblastic
leukemia (CLL) [116]. With respect to LMD spreading as a late-stage complication to
systemic cancers, lymphoma (specifically NHL), leukemia (ALL), and multiple myeloma
comprise some of the common primary etiologies in addition to some of the solid tumor
cancers as detailed in previous sections [1].
Regarding incidence, NHL is the most common hematologic malignancy, contributing
to around 4% of cancer diagnoses in the United States, with about 77,000 reported cases
in 2020. Globally, NHL diagnoses reached closer to 500,000 cases in 2018. It is estimated
that the NHL was responsible for around 250,000 deaths worldwide in 2018. This value
comprises 2.6% of annual mortalities attributable to cancer. In the United States, the 5-year
survival rate for NHL-diagnosed individuals was 72.7% (83.5% stage I, 63.3% stage IV)
between 2010 and 2016. The average diagnosis age is around 67 years old [117]. Lym-
phomagenesis, or the development of lymphoma, is the result of complex genetic and
environmental interactions, including lymphocyte signaling, transcription factor regula-
tion, and apoptotic mechanisms that synergistically result in the transformation of T and B
lymphocyte cells [118]. Tumorigeneses consist of uncontrolled lymphocyte proliferation
associated with distorted signaling pathways [119]. Similar to other cancer types, the gold
standard for a likely lymphoma diagnosis is an excisional biopsy at the level of the lymph
node [115]. Although fine needle aspiration or partial biopsy present possible less invasive
alternatives to open excisional biopsy, the former procedures neither provide the same
level of sensitivity nor specificity. Moreover, extraction of adequate nodal structures pro-
vides not only improved diagnosis but also benefits staging assessment and management
planning [120]. Imaging modalities for early lymphoma detection and subsequent interim
and remission monitoring involve a combination of CT and [18F]FDG-PET scans [121].
The PET-CT protocol has increasingly become the standard of care for lymphoma patients
as it provides both an anatomical and functional frame of reference [122]. However, the
frequency and duration of interim and remission imaging conventions are less established.
The benefit versus cost of periodic imaging is unclear given differing result-based guide-
lines [123]. Staging and grading the lymphoma case adds another factor to consider, as this
will play a role in the rate of lymphoma progression and whether or not these changes are
detectable under image guidance.
Of note, diffusion-weighted MRI is particularly useful in the detection of primary
CNS lymphoma. Primary leptomeningeal lymphoma comprises a small subset of primary
CNS lymphomas. Leptomeningeal involvement in lymphoma is exceedingly rare, only
occurring in 6% to 8% of NHL patients. However, the prevalence of LMD in NHL accounts
for 5 to 30% of all LMD metastatic cases, with a median prognosis of 2.6 months of
survival [1]. Consequently, LMD metastasis presents a poor prognosis, with an overall
survival estimated at less than 6 months in duration [124]. Given that specific lymphoma
variants have relatively higher rates of CSF dissemination, CSF cytology remains a crucial
Curr. Oncol. 2023, 30 5920

diagnostic tool for leptomeningeal lymphoma [125]. Unfortunately, multimodal diagnostics

in the form of CSF analysis and focal MRI detect leptomeningeal involvement in 7% to 42%
of patients, thereby indicating observable variation in accuracy [124]. Compared to solid
tumor cancers, LMD from lymphoma occurs more often in the absence of systemic disease
or parenchymal involvement and, at times, during remission.
Lymphoma-specific cell markers are numerous secondary to the quantity of subtypes
possible. B-cell markers include CD20, Pax-5, CD79a, Oct-2, and BOB.1. Hodgkin lym-
phoma markers include CD15, CD30, and CD57. T/NK-cell markers include CD2, CD5,
and CD4. The absence of both CD4 and CD8 is a hallmark of T-cell lymphoma [126].
Standard of care treatment for lymphoma patients is multimodal and comprises both
chemotherapy and radiotherapy in addition to antibody-drug conjugates (immunother-
apy) [119]. Since 2018, brentuximab vedotin, an anti-CD30 antibody-drug conjugate, has
been FDA approved for certain lymphoma subsets. Brentuximab vedotin has proven to
be efficacious in treatment and has a clinically safe toxicity threshold [120]. Rituximab,
which targets CD20, is a relatively more established antibody treatment against NHL [127].
As previously stated, CSF analysis is a prioritized diagnostic mode in dealing with pri-
mary central nervous system lymphomas. More specifically, microRNA profiles have been
demonstrated to be accurate in detecting primary central nervous system lymphoma in
addition to other CNS/neurological disorders. Some of these markers include miR-21,
miR-19, and miR-92a. Subsequent miRNAs have been shown to result in 95.7% sensitiv-
ity and 96.7% specificity [128]. Additionally, activated nuclear factor kappa-B is another
marker highly reminiscent of primary central nervous system lymphoma. Current clinical
trials have aimed to examine the underlying mechanisms behind the efficacy of Bruton’s
TKIs in the management of this lymphoma subset [129]. Overall, the use of these noninva-
sive biomarkers in conjunction with imaging monitoring and appropriate treatment has
provided improved outcomes in recent years.
With respect to leukemia, the Global Cancer Observatory (GCO) observed a global inci-
dence of around 474,000 cases. ALL and AML have a probable likelihood of manifesting in
both children and adults, reflecting a bimodal age distribution. Conversely, CML and CLL
are more commonly diagnosed in older populations. There were an estimated 61,000 newly
diagnosed cases of leukemia in 2021 based on the Surveillance, Epidemiology, and End
Results (SEER) database, contributing 3.2% of all cancer diagnoses. The estimated number
of deaths associated with leukemia amounted to 23,660 known deaths, which contributes
to 3.9% of all cancer-related deaths [130]. Suspected leukemia can first be detected through
an abnormal complete blood count (CBC), specifically in the form of leukocytosis or an
elevated white blood cell count (WBC) [131]. Further suspicions of leukemia are confirmed
through additional blood testing, flow cytometry analysis, and bone marrow sampling.
Imaging in the form of CT/MRI is more commonly employed for CNS diseases involving
leukemia. MRI (conventional, post-contrast, MR venography, and diffusion-weighted MRI)
is particularly critical to the early detection of CNS lesions, which are often treatable [132].
Since imaging abnormalities indicative of CNS involvement in leukemia vary, radiologic
findings have to be corroborated with lab work and symptoms for a timely diagnosis.
Regarding biomarkers, CNS-associated leukemia is accompanied by elevated expression of
adhesion molecules from these leukemic cells, including VLA-4, ICAM-1, VCAM, L-selectin,
PECAM-1, CD18, LFA-1, CD58, CD44, and CXCL12 [133]. These leukemic cells also secrete
VEGF-A, resulting in disruption of the BBB and infiltration into the CSF. As a result, CSF
cytology remains a necessary component in the diagnostic workup of lymphoma with CNS
extension. Biopsy and/or bone marrow aspiration are another relatively more invasive
gold standard in the early detection of lymphoma of all subtypes. Treatment options will
usually entail chemotherapy, with radiotherapy more often employed to prevent metastasis
or treat CNS infiltration [131]. Other treatment options include hematopoietic stem cell
transplantation (typically allogenic bone marrow transplantation) and monoclonal antibod-
ies [134]. However, high-dose chemotherapy and stem cell transplantation are less suitable
for older, comorbid populations. Hypomethylating agents (HMAs) and medications, such
Curr. Oncol. 2023, 30 5921

as venetoclax (a BCL-2 apoptotic regular protein inhibitor), are promising new noninvasive
additions to current treatment regimens [135,136]. Furthermore, FMS-like tyrosine kinase
3 (FLT3) and isocitrate dehydrogenase inhibitors have been proven to work as successful
therapies alone and in conjunction with other modalities in a percentage of lymphoma
patients. Unfortunately, these developing treatments also present their own shortcomings,
such as mechanisms of resistance to said medications [137].
Behind NHL, multiple myeloma ranks as the next most common hematologic cancer
type. However, multiple myeloma only comprises 1% of all cancer cases. Multiple myeloma
is characterized by abnormalities in plasma cells within the bone marrow, resulting in
uncontrolled proliferation [138]. It is estimated there were around 24,000 to 30,000 annual
cases, accompanied by 12,650 deaths, in 2016. Similar to lymphoma, the median age at
diagnosis of multiple myeloma has been calculated to be 66 to 70 years old. Across multiple
hematologic and solid tumor cancers, survival rates have been trending towards extended
periods of survival given the increased availability of effective therapies. Median survival
in multiple myeloma patients has approximately doubled in duration from 12 months prior
to the year 2000 to 24 months after 2000 [139].
The diagnosis of multiple myeloma results from a summation of a history/physical,
lab work including urinalysis and bone marrow biopsy, and radiography [140]. The extent
of organ damage dictates the urgency and severity of treatment. Organ damage indicates
the urgency of treatment. Along with organ damage, bone disease is a common multiple
myeloma feature, whereby skeletal radiography is necessary for detection [141]. Previous
conventional radiography consisted of a generalized skeletal x-ray series. However, as this
procedure alone lacks the sensitivity of osteolytic lesion detection, radiographic protocols
have progressed to multiple, more sophisticated imaging modalities, including whole-body
low-dose CT, whole-body MRI, and PET/CT [142]. These imaging techniques range in
time, sensitivity, and cost; they should be used both together and under context specific
criteria. The standard of care for newly developed multiple myeloma consists of triplet
therapy along with high-dose chemotherapy and autologous stem cell transplantation [143].
Triplet therapy refers to treatment with a corticosteroid, an immunomodulator, and a cancer
targeting drug, such as proteasome inhibitors [144]. The use of monoclonal antibodies,
such as daratumumab and elotuzumab, which target CD38 and SLAMF7 markers, has
been effectively integrated into clinical treatment [145]. However, the same issue is present
across multiple antibody treatments, where clonal selection for resistance in multiple
myeloma cells arises. B-cell maturation antigen (BCMA)-targeted therapies are potentially
new alternatives that have demonstrated efficacy without excessive toxicity [146]. LMD
metastasis/CNS involvement cases from primary multiple myeloma are not frequent and
are often evidenced through case reports. Medication penetration through the BBB is a
consistent obstacle once malignancies metastasize to the CNS. Novel therapies are currently
being studied in both preclinical and clinical settings to overcome this barrier. Thalidomide
and pomalidomide have proven to show adequate penetration. Moreover, marizomib
is a proteasome inhibitor that also demonstrates similar penetrative qualities [147]. As
stated, LMD metastasis from hematologic cancer is a relatively rare scenario. The lack of
studies regarding appropriate treatment, dosing, and overall approach to LMD highlights
a demand for further study in this context.

7. Leptomeningeal Mimics
Thus far, this review has elucidated the pathophysiology and therapies of the most
common forms of LMD, with a closing discourse on hematologic origins. Therefore, a brief
discussion of rarer yet equally intriguing presentations of LMD will also be introduced.
To note, leptomeningeal involvement need not be attributed to metastatic or malignant
etiologies. Various diseases may present with leptomeningeal involvement, mimicking
LMD. Currently, these have been sparsely described in the literature, primarily in the
context of case reports, including rare instances of neuroborreliosis, giant cell arteritis, and
sarcoidosis [148–150].
Curr. Oncol. 2023, 30 5922

In particular, sarcoidosis appears to be the most widely encountered mimic of LMD

in instances of CNS involvement. Sarcoidosis is well acknowledged as a systemic ailment
characterized most aptly upon histological observation of non-caseating sarcoid granulo-
mas [151]. Its prevalence ranges from 0.001% to 0.04% of individuals, more widely affecting
females and those aged 20–40 [152,153]. To date, it carries an unexplainable etiology, shift-
ing considerable diagnostic reliance on biopsy. The majority of sarcoidosis cases affect the
respiratory system in nearly 90% of individuals, inadvertently lowering suspicion in the
context of other organ involvement [151]. However, in the context of CNS involvement, it
is particularly salient to acknowledge any form of systemic involvement prior to the onset
of neurological symptoms. This can provide considerable guidance towards the diagnosis
of sarcoidosis pertinent to the regions of the CNS—neurosarcoidosis [152,154].
Neurosarcoidosis can affect the brain, cranial nerves, meninges, and spinal cord [154].
Symptomatic presentation can manifest as generalized neurological symptoms including
headache, diplopia, and vertigo, among others, providing low utility regarding neurosar-
coidosis diagnosis, though the sequence of region involvement can provide more value in
this; moreover, the number of systems involved has displayed a notable association [154].
For example, in a prospective study of 166 patients, systemic manifestation in 100 cases
coincided with, in 55 cases preceded, and in only 10 cases followed CNS involvement
chronologically [154]. Other pertinent biomarkers included MRI and CSF abnormalities,
as well as LMD. This involved hyperproteinorrachia, hypoglycorrhachia, and elevated
angiotensin converting enzyme (ACE) CSF levels [154]. MRI observations included re-
gional enhancement on T1-weighted MRI scans following gadolinium administration [155].
Overall, it veers toward a rule-out approach, requiring sound exclusion for other etiologic
explanations. Current treatment options are rarely definitive and exist primarily in the
form of inflammatory control, as with other forms of sarcoidosis, including glucocorticoids
and inflammatory modulators, such as tumor necrosis factor (TNF) alpha inhibitors [156].
Rarer instances of LMD mimics are relatively sparse, though these will be discussed.
As elucidated, neuroborreliosis has been accounted for in the literature as a potential
condition highly reminiscent of leptomeningeal involvement. Neuroborreliosis entails the
neurological affiliation of infection by the genus Borrelia, colloquially acknowledged as
Lyme disease. Such affiliation following CNS involvement occurs in up to 15% of borrelia
infections, often manifesting as non-specific neurological symptoms including meningitis,
cranial nerve deficits, and radiculopathy. The gold standard of diagnosis for LMD, MRI, has
little distinctive capacity between neuroborreliosis and LMD, thereby producing complex
cases in the current literature. Caretakers should then be highly suspicious of the former
in the setting of potential signs of vector-borne infections, such as erythema and rash, as
reported previously. Upon suspicion, further serological testing via antibody detection
of borrelia has more definitively ruled out a diagnosis of neuroborreliosis. Treatment
intuitively entails antibiotic therapy, which exclusively resolves neuroborreliosis as opposed
to LMD.
Giant cell arteritis has likewise been scantily reported, though it has appeared as
a potential mimic of LMD. Giant cell arteritis (GCA), synonymously termed temporal
arteritis, is a vasculitis affecting medium- and large-sized vessels, quite often the external
carotid artery and its branches, namely the temporal branch. A primary concern in GCA
is that of ischemic optic neuropathy, which is understandably observed in the form of
vision loss. Indeed, the case report detailing the leptomeningeal mimicking characteristics
of giant cell arteritis was characterized by a similar presentation with progressive vision
loss. Additionally, MRI may reveal nodular enhancement, more so localized to the optic
nerve sheaths, which is also reminiscent of sarcoidosis. Temporal artery biopsy is the most
conclusive modality for diagnosing GCA, though the path towards this diagnosis remains
relatively difficult to land upon. Similar to sarcoidosis and other inflammatory disorders,
steroid treatment has demonstrated efficacy.
Curr. Oncol. 2023, 30 5923

8. Conclusions
Although LMD metastasis from both solid tumor cancers and hematologic malig-
nancies is comparatively more frequently occurring than primary diffuse leptomeningeal
gliomatosis, it still presents as a late-stage complication in these cancer types in a small
subset of metastatic cancer patients (approximately 5%), with diagnosis often occurring
by way of post-mortem autopsy [157,158]. The overall prevalence of LMD accounts for
approximately less than 10% of diagnosed cancer cases [50]. Interestingly, LMD occurrence
has been more frequent in recent years due to the extended outcome survival for cancer
patients as a whole [1]. Regardless of primary etiology, early detection and treatment
of CNS involvement have proven to provide relatively improved outcomes, even if still
measured at a median of 3 to 6 months in duration. Survival periods are not long by nature,
but they have lengthened as the overall number of cases of LMD has increased. This trend
is in part due to the advances in detection strategies that utilize a combination of MRI, CT,
and CSF cytopathology by way of lumbar puncture analysis. Imaging is not without limi-
tations, however, as MRI detection has a rated sensitivity and specificity of 75% and 77%,
respectively [158]. Additionally, CSF samples require more than one round. CSF analysis
remains the gold standard and is able to mediate unclear imaging enhancements. In recent
advances, genomic analysis of ctDNA has shown itself to be a promising biomarker for
neurological malignancies [159]. Treatment for LMD has likewise progressed from more
systemic forms to targeted therapy based on the primary cancer types. Utilizing inhibitors
against cancer-specific markers overcomes the limitations of widespread chemotherapy,
which fails to fully pass the BBB [160]. Improved therapy for LMD requires progress in
targeting specific cancer types. As stated, LMD metastasis is a late-stage complication
of several different primary cancers. Prognosis is not optimal as LMD diagnosis may
reflect failed therapy to control metastasis; however, medical advancements are trending
towards more accurate and salient forms of detection and treatment of not only metastatic
malignancies but also CNS-specific malignancies, such as LMD.

Author Contributions: Conceptualization, B.L.-W., A.N. (Andrew Nguyen) and A.N. (Alexander
Nguyen); investigation, A.N. (Andrew Nguyen), A.N. (Alexander Nguyen), O.T.D., P.D.D., J.C.R.
and N.B.G.; writing—original draft and preparation, A.N. (Andrew Nguyen), A.N. (Alexander
Nguyen), O.T.D., P.D.D., J.C.R. and N.B.G.; writing—review and editing, A.N. (Andrew Nguyen),
A.N. (Alexander Nguyen), O.T.D., P.D.D., J.C.R., N.B.G., K.P. and B.L.-W.; supervision, B.L.-W. All
authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Ethical review and approval were waived for this study as
this was a review study.
Informed Consent Statement: Not applicable.
Data Availability Statement: No datasets were utilized.
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

LMD Leptomeningeal disease

MS Multiple sclerosis
CNS Central nervous system
NHL Non-Hodgkin’s lymphoma
ALL Acute lymphoblastic leukemia
CSF Cerebrospinal fluid
CN Cranial nerve
NCNN National Comprehensive Cancer Network
KPS Karnofsky performance scale
SWS Sturge-Weber syndrome
MRI Magnetic resonance imaging
Curr. Oncol. 2023, 30 5924

CEA Carcinoembryonic antigen

ICP Intracranial pressure
VPS Ventriculoperitoneal shunt
WBRT Whole brain radiation therapy
CSI Craniospinal irradiation
ICI Immune checkpoint inhibitor
RCT Randomized controlled trial
MC Meningeal carcinomatosis
LBM Leptomeningeal breast cancer metastasis
ER Estrogen receptor
PR Progesterone receptor
HER2 Human epidermal growth factor receptor 2
EGFR Epidermal growth factor receptor
BBB Blood brain barrier
ctDNA Tumor derived DNA
HCB Hot cross bun
LLM Leptomeningeal lung cancer metastasis
NSCLC Non-small cell lung cancer
BM Brain metastases
ALK Anaplastic lymphoma kinase
SCLC Small cell lung carcinoma
LUAD Lung adenocarcinoma
LUSC Lung squamous cell carcinoma
ACTA2 Actin gene
EpCAMs Epithelial cell adhesion molecules
TKI Tyrosine kinase inhibitor
LMM leptomeningeal melanoma metastasis
MCAM Melanoma cell adhesion molecule
MMP Metalloproteinase
VEGFA Vascular endothelial growth factor A
CTC Circulating tumor cells
NGS Next Generation Sequencing
ddPCR Droplet digital PCR
TT Targeted therapies
GBM Glioblastoma
CML Chronic myelogenous leukemia
CLL Chronic lymphoblastic leukemia
GCO Global cancer observatory
SEER Surveillance, epidemiology, and end results
CBC Complete blood count
WBC White blood count
HMA Hypomethylating agent
FLT3 FMS-like tyrosine kinase 3
BCMA B-cell maturation antigen
ACE Angiotensin converting enzyme

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