Discussion
In this report, we presented the case of an infant with SHH-activated
embryonal tumor that developed as an isolated CPA lesion, diagnosed
using both pathological and molecular diagnostics. Molecular
classification using DNA methylation analysis has emerged as a novel
diagnostic tool because most CNS tumors including medulloblastoma may
have distinct methylation profiles. With this analysis, several previous
reports have been documented about “medulloblastoma” occurring in
different regions of the cerebellum or fourth ventricle. Liu et al.
reported seven cases of embryonal tumors in the pineal region,
classified as “Medulloblastoma,
WNT-activated (MB-WNT).” All cases exhibited missense mutations in
exon3 of CTNNB1 and three cases exhibited monosomy 6, which is
unusual in pineoblastomas but typically observed in WNT-activated
medulloblastomas3). Arnault et al. also reported the
case of a 5-year-old girl with an embryonal tumor in the sellar and
suprasellar regions, which was initially diagnosed as CNS-PNET but later
classified as a WNT-activated medulloblastoma based on DNA methylation
analysis4). In terms of SHH-activated medulloblastoma,
Grammel et al. presented evidence of tumor development outside the
cerebellum. In their report, granule neuron precursors, known to be the
cells of origin of SHH medulloblastoma, were observed in the cochlear
nuclei of the brainstem and was suggested to be the cellular origin of
the tumor5). The tumor in the present case appeared to
have developed from the ventral side of the pons, which is not
concordant with the location of the cochlear nuclei in the pons.PTEN alteration possibly led to mismigration of granule cells,
leading to tumor occurrence in an unusual location, because the gene may
play a critical role in cell migration during brain
development6).
In our case, the patient was diagnosed with Cowden syndrome based on
genetic testing of the tumor, which may also support the diagnosis of
medulloblastoma. Cowden syndrome is an autosomal dominant genetic
disease in which multiple hamartomatous lesions. PTEN mutations
have been identified as causative genetic alterations in 80% of the
patients; malignancies occur frequently in young adulthood, and the most
common sites are the breast, thyroid, and uterus7).
Development of malignant brain tumors is extremely rare in patients with
Cowden Syndrome.
Only six cases of Cowden syndrome with intracranial embryonal tumors
have been reported till date, and all of them were actually
medulloblastomas8)9). In these reports, all patients
with Cowden syndrome were diagnosed with medulloblastoma at the age of
<2 years. Among the patients with detailed information
regarding pathology and molecular subgroups, two were diagnosed with
pathologically confirmed desmoplastic/nodular subtype or MBEN, and four
were diagnosed with SHH-activated type medulloblastoma based on
molecular analysis8). These clinical and molecular
features are consistent with those in our case, except for the site of
tumor development.