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.