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Page 4 of 20 Pellerino et al. J Cancer Metastasis Treat 2020;6:41 I http://dx.doi.org/10.20517/2394-4722.2020.80

Complement component 3 (C3), which is produced by cancer cells in the CSF, is upregulated in LM models
from lung and breast cancer. In particular, C3 promotes the disruption of blood-CSF barrier, leading to the
[39]
passage of some mitogens, such as amphiregulin, that promotes tumor cell growth within leptomeninges .
Similarly, Matrix Metalloproteases (MMPs) type 9, A Disintegrin and Metalloproteases (ADAMs) type
8 and 17 interfere with the integrity of the blood-CSF barrier, facilitating the passage of tumor cells into
[40]
the subarachnoid space . Some driver mutations select clonal tumor cells making them more prone to
[41]
metastasize to the CNS. Brastianos et al. showed that distinct genetic alterations were not detected in the
matched primary-tumor sample in 53% of 86 patients with BM, while spatially and temporally separated
BM were genetically homogenous and shared similar druggable pathways, including PI3K/AKT/mTOR,
CDK, and HER2/EGFR. Further investigations have revealed three regions with significantly higher
[42]
amplification in BM from NSCLC, including MYC, YAP1, and MMP13, and deletions in CDKN2A/B .
Thus, the response to targeted therapies in BM or LM not necessarily recapitulate the response of the
primary tumor: profiling the BM and LM might be advantageous in planning therapeutic interventions,
predicting response, and discovering new targets that could be absent in the primary disease.

The acquired resistance to first-generation targeted therapy in NSCLC has been suggested to promote LM.
[43]
Nanjo et al. described that acquired resistance to gefitinib is characterized by an upregulation of MET
and absence of T790M mutation. Moreover, the T790M mutation has not been identified neither in BM or
[46]
[47]
LM [44,45] , nor in CSF of patients who have developed LM following EGFR TKIs . Jiang et al. reported a
lower frequency of T790M mutation (21%) and a higher frequency of MET amplification (39%) in the CSF,
[48]
suggesting that MET amplification could confer a major risk of leptomeningeal invasion .
Clinical and radiological diagnosis of leptomeningeal metastases
Symptoms from LM are typically multifocal due to the involvement of different segments of the neuroaxis.
Spinal cord and nerve roots are the most frequent sites of LM (60%), followed by cranial nerves (35%) and
[49]
cerebrum (15%) . Table 2 summarizes the most common symptoms from LM. As any site in the CNS
may be involved, the evaluation of a patient with suspected LM is difficult, and signs and symptoms may be
shared by BM, or mimic treatment-related toxicities or neurological paraneoplastic syndromes. Therefore,
the neurological examination is crucial and should be performed by an expert neurologist. However, LM is
a complication of solid tumors that is primarily being treated by medical oncologists, thus a standardized
clinical evaluation is needed especially during follow up. The Neurologic Assessment in Neuro-Oncology
(NANO) scale was drafted by a group of physicians, including neurologists, medical oncologists, radiation
oncologists, and neurosurgeons, with expertise in neuro-oncology, and was tested during routine
examination, reporting an objective clinician-reported outcome of neurologic function with high inter-
observer agreement [50,51] . Unfortunately, the NANO scale is not useful enough, due to the low sensitivity to
detect the multilevel involvement of the CNS typically seen in LM. With this regard, the Leptomeningeal
Assessment for Neuro-Oncology (LANO) group has developed a standardized assessment with several
domains, such as gait, strength, sensation, vision, eye movement, facial strength, hearing, swallowing,
level of consciousness and behavior, which may be graded as 0 (normal), 1 (slight abnormal), 2 (moderate
abnormal) and 3 (severe abnormal) . However, the LANO scale needs to be validated, and other tools are
[52]
being used to improve the diagnosis of LM.

[53]
Brain and spinal cord MRI with contrast enhancement is mandatory for the assessment of suspected LM .
Contrast-enhanced T1-weighted and fluid-attenuated inversion recovery (FLAIR) sequences are the most
[54]
sensitive to show LM . Linear or nodular enhancing lesions of the cranial nerves and spinal nerve roots
(e.g., cauda equina), brain sulci and cerebellar folia are the most common findings [Figures 1 and 2].
[55]
Nodular lesions typically are small (< 5 mm) with a complex geometry, and to measure the tumor burden
is difficult. As a result, the RANO Leptomeningeal Metastasis Group proposed a LANO scorecard for
diagnosis of MRI in LM patients, but most of the raters experienced problems with the instructions on the