Definition: Medulloblastoma, WNT-activated, is an embryonal tumor that originates from the dorsal brainstem and is characterized by the activation of the WNT signaling pathway.
Localization: WNT-activated medulloblastomas are found around the foramen of Luschka, seemingly originating from the brainstem or cerebellum, or in the cerebellar midline, typically adjoining the brainstem. They often extend towards the cerebellopontine angle or cerebellar peduncle in many cases.
Clinical Features: Most patients exhibit symptoms of increased intracranial pressure due to non-communicating hydrocephalus, caused by the primary tumor blocking the fourth ventricle.
Imaging: Neuroimaging reveals WNT-activated medulloblastomas located in the cerebellar midline or cerebellopontine angle, often in close proximity to the brainstem. These tumors have a relatively permeable blood–brain barrier compared to other types of medulloblastoma, leading to very bright enhancement on imaging.
Spread: It is uncommon for patients with WNT-activated medulloblastoma to present with leptomeningeal metastases.
Epidemiology: WNT-activated tumors represent about 10% of all medulloblastomas. They typically occur in children between the ages of 7 and 14 years and account for 15–20% of adult medulloblastomas. There is a slight female predominance in these cases. WNT-activated medulloblastomas are very rare in infants.
Etiology: Most WNT-activated medulloblastomas are sporadic, and their exact cause remains largely unknown. A small subset of these tumors is associated with constitutional mismatch repair deficiency syndrome, occurring in individuals with germline APC mutations and an increased risk of colon cancer.
Pathogenesis: WNT-activated medulloblastomas transcriptionally resemble progenitor cells from the lower rhombic lip-derived mossy fiber neuron lineage, suggesting an origin from the dorsal brainstem. Their DNA methylation profile and transcriptional signatures, distinct from other medulloblastoma groups, provide strong evidence for this cell of origin.
Genetic Profile: Large next-generation sequencing studies have shown that 86-89% of WNT-activated medulloblastomas have somatic mutations in exon 3 of CTNNB1. In cases without CTNNB1 mutations, most arise in children with pathogenic germline APC mutations. Other somatic mutations found in WNT-activated medulloblastomas include genes encoding components of the SWI/SNF nucleosome-remodeling complex (SMARCA4, ARID1A, ARID2 in 33% of cases), DDX3X (36%), CSNK2B (14%), TP53 (14%), KMT2D (14%), and PIK3CA (11%). A characteristic genetic feature of WNT-activated medulloblastomas is monosomy 6 on an otherwise diploid genome, observed in about 83% of cases.
Macroscopic Appearance: Medulloblastomas typically appear as friable pink masses. Intratumoral hemorrhage is notably associated with WNT-activated medulloblastomas during surgery.
Histopathology: Nearly all WNT-activated medulloblastomas exhibit classic morphology. Anaplastic forms of WNT-activated tumors have been reported but are rare. Desmoplastic/nodular medulloblastomas are not seen in this group.
Immunophenotype: Activation of the WNT pathway is indicated by either universal or patchy β-catenin immunoreactivity in the nuclei of tumor cells. In contrast, medulloblastomas of other molecular groups show cytoplasmic expression of β-catenin.
Diagnostic Molecular Pathology: More than 80% of WNT-activated medulloblastomas harbor CTNNB1 exon 3 mutations and monosomy 6 on a diploid genome. These genetic alterations help identify WNT-activated medulloblastomas, but DNA methylation profiling is the gold standard for determining the medulloblastoma group or subgroup status. Molecular group assignment methods include array-based DNA methylation analysis, array- and sequencing-based RNA expression analysis, NanoString analysis, and minimal methylation classifier assays. Immunohistochemistry can also differentiate between WNT, SHH, and non-WNT/non-SHH medulloblastomas. Two molecular subgroups, WNT-α and WNT-β, have been proposed: WNT-α tumors, which show monosomy 6, arise in children, while WNT-β tumors, typically diploid for chromosome 6, occur in older children and young adults.
Staging: Clinical staging procedures involve MRI examinations of the CNS with contrast agents, complemented by lumbar puncture for postoperative cerebrospinal fluid cytology. The postoperative staging system, developed by Chang and others in 1969, defines metastatic spread as follows:
- M0: No evidence of subarachnoid or hematogenous metastasis
- M1: Microscopic tumor cells found in the cerebrospinal fluid
- M2: Gross nodular seeding in the cerebellar/cerebral subarachnoid space or in the third or lateral ventricles
- M3: Gross nodular seeding in the spinal subarachnoid space
- M4: Metastasis outside the cerebrospinal axis
Prognosis and Prediction: The prognosis for children with WNT-activated medulloblastoma is excellent despite the CNS WHO grade, with overall survival rates close to 100% due to current surgical and adjuvant therapeutic regimens. Tumors with germline APC mutations or CTNNB1 mutations also have excellent outcomes. However, adult patients with WNT-activated medulloblastoma do not fare as well. Unlike TP53 mutations in SHH-activated medulloblastomas, somatic, usually heterozygous TP53 mutations in WNT-activated medulloblastomas do not worsen prognosis.
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