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ensuring favorable outcomes, as surgical resection is generally more successful when tumors are smaller,
confined to a single location, and less entwined with critical neural structures.

Despite a general awareness of the importance of establishing a prompt diagnosis for pediatric brain
tumor care, delay in time to diagnosis is common with pediatric brain tumor patients, as children have a
[9]
unique capacity to tolerate intracranial volume and pressure changes with minimal outward symptoms .
Additionally, the immature nature of the nervous system in infants makes clinical screening for brain
tumor-related symptoms challenging. Widespread radiographic screening of children, be it with computed
tomography or magnetic resonance imaging, is impractical due to the risks of radiation exposure to the
developing central nervous system, neurotoxic effects of early anesthetic exposure, and prohibitive diagnostic
costs [10-12] .

As such, a minimally invasive, reliable, and cheaply implemented screening tool has become a great clinical
need for physicians and researchers seeking to improve early tumor detection, develop minimally invasive
methods for molecular stratification of tumors, and allow for reliable post-treatment screening in pediatric
brain tumor populations. Numerous permutations exist for researchers seeking to discover and validate
novel biomarkers, as potential tumor markers need to be examined in different biofluid reservoirs and
with different analytic techniques. Each variation in biomarker sampling and analysis exposes different
advantages and limitations that researchers and clinicians must be cognizant of as they search for accurate
and realistically deployable brain tumor biomarker assays. The authors will review here the history of
biomarker development for pediatric brain tumors to date, the limitations and advantages of current target
biofluids, promising biomarkers for the most prevalent pediatric brain tumors, and the major limitations of
biomarker development in pediatric populations.

Historical biomarkers
Attempts to acquire objective evidence of a tumor from extra-tumor biofluids date back at least 100 years,
beginning with cerebrospinal fluid (CSF) cytology. Tumor cytology is the oldest and most well-understood
[13]
method for detecting and differentiating pediatric brain tumors via a biofluid . The use of cytology to
[14]
diagnose tumors in a minimally invasive manner dates back to the 19th century . The process for acquiring
CSF samples for cytologic analysis has the benefit of being relatively simple to perform and widely available
in most regions of the world. In order to acquire a CSF sample, a lumbar puncture is performed with a
sterile 20-22-gauge needle at or below the L2/L3 interlaminar space. Ventricular CSF samples have been
used, as well, for CSF cytology; but the sensitivity of samples acquired from cerebral ventricular punctures
is significantly lower than samples drawn from the lumbar cistern, likely due to sedimentation of tumor
[15]
cells into the dependent lumbar cistern . CSF samples are then fixed and processed for light microscopic
evaluation or flow cytometry. CSF cytology can provide pathologic diagnoses in many oncologic cases.
Immunohistochemical assays are also possible, making the cytologic analysis of CSF somewhat comparable
to tissue biopsy in the range of qualitative information it can provide. However, CSF cytology has a low
sensitivity (45%), unless performed repeatedly on the same patient, making it an inaccurate and impractical
brain tumor screening modality by itself [16,17] .

Arguably, modern pediatric intracranial tumor serum biomarker assay development began in the 1960s and
70s in the field of germ cell tumor diagnostics. Research with immunoperoxidase staining of testis germ
cell tumors revealed excesses in alfa-fetoprotein (AFP) and beta human chorionic gonadotropin (βHCG)
[18]
production within the tissues of some tumor types . Immunostaining and radioimmunoassay techniques
quickly proliferated for these compounds; and by the mid-1970s, pathologists were able to utilize AFP, βHCG,
as well as other proteins, to distinguish endodermal sinus tumors, choriocarcinomas, dysgerminomas, and
teratomas on immunohistochemical review and via serum-based tests.