To the editor,
Methylation-based classification stratifies supratentorial embryonal
tumors into 4 distinct entities, among which, CNS-neuroblastoma,FOXR 2-activated, and neuroepithelial tumors withBCOR -alteration, have been included in the new WHO
classification1,2. While the tool has emerged as an
important adjunct to tumor characterization in the modern era, its
performance and scope may be limited by the data used to train the
classifier. We share our challenges in characterizing a supratentorial
embryonal tumor that was ultimately successfully treated according to
its histology.
A 5-year-old boy presented with right-focal weakness for 8-months. A
8x7x6.5-cc mass in the left-frontoparietal region (Fig.1A) was
completely resected and diagnosed as CNS-neuroblastoma (Fig.1B,C).
Spine, CSF and whole-body PET were clear. Methylation-based classifier
failed to characterize this tumor. Unsupervised clustering grouped it
closest to embryonal tumors with multi-layered rosettes (ETMR) (Fig.1D).
No multi-layered rosettes were detected, LIN28 was negative, INI-1 and
mismatch-repair stains were retained. Copy number aberrations (CNA)
included losses in chromosomes 3p, 9 (including the CDKN2A/Blocus), 11q (partial) and 19q (partial) and focal gains on chromosome-19
(Fig.1E), but no amplification of the chromosome-19 microRNA-cluster
(19MC) (Fig.1F). MYC or MYCN were not amplified. MGMT
promoter was methylated (Fig.1G). Repeated attempts at sequencing
failed. He was treated with craniospinal irradiation (23.4Gy,
13-fractions; tumor-bed boost 14.4Gy, 8-fractions). Adjuvant
chemotherapy included vincristine, cisplatin and cyclophosphamide. The
child remains in complete remission after 2-years.
CNS-neuroblastoma presents at a median age of 5-8 years, shows female
preponderance, and predilection for the fronto-parietal
region3,4. Radiology is heterogeneous, frequently
including solid-cystic components with central necrosis and haemorrhage.
Methylome analysis is the method of choice for
diagnosis5. CNAs include 1q gain, aberrations/losses
in 16q, 3p and 6q, and gains in chromosomes 17q and
81,5,4. Recent analyses incorporating accurate
molecular analyses suggest 5-year survival
>80%5. In contrast, ETMR is a tumor of
infants and younger children, characterized by multi-layered
pseudo-rosettes, expression of LIN28, amplification of C19MC and dismal
outcomes6,7. CNAs include gain in chromosome 2 and 1q,
and losses in 6q. Rare (<10%) subsets lacking C19MC
amplification cluster with other ETMRs on methylome-analysis and are
enriched for DICER1 variants (chromosome-14), or harbour
amplifications in other micro-RNA clusters on
chromosome-136.
The embryonal tumor in our patient failed characterization by
methylome-analysis. While the histo-morphological best-fit was
CNS-neuroblastoma, unsupervised clustering was closest to ETMR. The CNAs
did not match either diagnosis. Interestingly, the MGMT promoter was
methylated, which has only been rarely reported in embryonal tumors, and
despite indicating sensitivity to temozolomide and lomustine, has not
been predictive of survival8,9. Overall, this
suggested unique biology, and that this novel entity is not currently
represented in the classifier database.
As the use of methylome-based tumor classification is currently limited
to specialized centers in Europe, North America and Australia, it is not
surprising that rare tumor subsets from other demographic populations
may be under-represented. Limitations have been apparent for rare tumors
like NTRK-fused gliomas10 and those arising from
germline defects like mismatch-repair deficiency11.
Twinning initiatives and collaboration between centers of excellence in
the West and the large-volume centers in developing countries are needed
to advance this diagnostic tool and benefit the entire spectrum of
children with CNS tumors.
Source of funding: AD is supported by the St. Baldrick’s
Foundation International Scholar Award (with generous support from the
Team Campbell Foundation; Grant number: 697257) and the SickKids
Research Training Center Clinician-Scientist Training Program (Fall 2019
award).
Acknowledgements: We are grateful to Dr Martin Sill (DKFZ,
Heidelberg) for analysing and confirming that methylation profile
similar to the index tumor was not identified in their database.
Consent: Informed consent was obtained from the parents for
publishing this case report.