CNS5:Medulloblastoma, WNT-activated: Difference between revisions

|PMID: 33681213

|PMID: 33681213

·      Monosomy 6 is the most frequently reported genomic alteration, occurring within 80-85% of cases and commonly co-occurring with ''CTNNB1'' somatic mutations. (PMIDs: 16567768; 28726821; 17172831; 30765705)

·      With the exception of monosomy 6, this medulloblastoma subtype usually has a balanced genome (PMID: 22832581)

|Yes – Monosomy 6 is associated with very good outcome in pediatric patients (PDQ, PMIDs: 24791927, 21267586, 17012043).

|Presence of monosomy 6 is frequently observed, and present in 80-90% of cases (PMID: 28726821).  This finding is much more common in pediatric patients and has been proposed as a marker for WNT subtype α.  

However, absence of monosomy 6 does not rule out the possibility of WNT-activated medulloblastoma (PMID: 28726821).  Furthermore, adult patients will be misdiagnosed if monosomy 6 is used alone as a diagnostic factor, as they cluster within WNT subtype β, which characteristically lacks this finding (PMID: 28609654).  

Outside of monosomy 6, other cytogenetic findings are rarely observed in this subtype (PMID: 23175120).

|Yes – Favorable prognosis (PMID: 31504825)

|~85% of cases (PMID: 28726821); Somatic

|5-10% (COSMIC; PMID: 28726821)

|Yes – Favorable prognosis (PMID: 31504825)

|Warrant germline evaluation if identified (PMID: 32239782, 28726821); LOF of APC  leads to nuclear accumulation of β-catenin, resulting in increased WNT  signaling (PMID: 29189165)

Approximately one third of medulloblastomas across all subgroups carry mutations in histone modifier genes, however, they are not unique to the WNT subtype (PMID: 29189165).

* Canonical WNT-pathway activation (PMID: 31921137)

* Chromosomes– assess for monosomy 6 (PMIDs: 32239782, 29027579)

* Chromosomal Microarray – assess for monosomy 6

* Sequence analysis (e.g. NGS) – assess for somatic mutations in ''CTNNB1'' and/or ''APC''

* DNA methylation profiling – tumor type and subtype classification by epigenetic signatures

* Transcriptomics – tumor type and subtype classification by gene expression signatures

* Germline variants in ''APC'', which most commonly cause Familial Adenomatous Polyposis, may also lead to the development of WNT-activated subtype medulloblastoma (PMIDs: 32239782, 30765705)

* DNA methylation profiling is considered to be the current gold-standard for determining MB subgroup and subtype (PMIDs: 23670100; 23291781) and is available clinically

* Good prognosis is currently thought to be due to alterations in tumour vasculature and its effects on the blood-brain barrier, making the tumor more accessible to systemic chemotherapies (PMID: 27050100)

* Somatic ''TP53'' mutations do not portend a worse prognosis (PMID: 23835706)

* Recent studies employing single-cell RNA-seq (PMID: 31341285) are revealing transcriptional and genetic heterogeneity within this and other MB subgroups

* Medulloblastoma is the most common malignant pediatric brain tumor, though it can also occur in adults (PMIDs: 29189165; 23175120; 30445539). Recurrent histopathologic, radiologic, and genomic findings have resulted in the establishment of four primary molecularly-defined subgroups: WNT-activated; SHH-activated and ''TP53''-wildtype; SHH-activated and ''TP53''-mutant; and non-WNT/non-SHH (PMID: 22358457). Somatic variants that cause activation of these pathways (e.g., gain-of-function variants in ''CTNNB1'' for the WNT pathway) are considered diagnostic. Of note, a subset of cases can be due to germline loss-of-function variants in the ''APC'' gene (which also result in activation of WNT signaling), which are representative of the spectrum of disorders known as Familial Adenomatous Polyposis (historically referred to as Gardner syndrome; MIM: 175100). In summary, medulloblastoma, WNT-activated, is an embryonal tumor originating in the dorsal brainstem characterized by activation of the WNT signaling pathway.

* This subtype accounts for approximately 10% of all medulloblastomas (PMIDs: 23175120, 22832581, 22358457, 22134537).

* Most frequently observed in older children (median age 10 years; PMIDs: 23175120, 22832581) with a balanced male:female ratio (PMID: 22134537); Of note, this medulloblastoma subtype rarely occurs in infants and rarely metastasizes (PMID: 31799776).

* Excellent prognosis for patients <16 years of age at diagnosis: >95% have a five-year overall survival (PMIDs: 16567768; 17172831; 16258095; 19197950)

* Accounts for ~15% of all adult medulloblastomas, which may have a worse prognosis than pediatric WNT-activated medulloblastoma (PMID: 28609654, 21632505; 26420814; 27106407)

* Cranial and spinal MRI are used for diagnosis (PMID: 30765705)

* Signs and symptoms (listed below) can increase in severity over weeks to months

* Signs and symptoms - Headache; Clumsiness; Fatigue; Nausea/vomiting; Declining motor skills and/or ataxia; Vision problems and/or strabismus; Hydrocephalus

* Laboratory findings - None

* Cerebellum, cerebellar peduncle or fourth ventricle (PMIDs: 32239782; 26338912)

* Origin: cells in the extracerebellar lower rhombic lip (PMID: 21150899)

* Metastases are much less likely to occur in this subtype relative to other MB subtypes; staging is performed using the Chang classification (PMID: 4983156)

* The WNT-activated subgroup is most commonly observed as an embryonal tumor with classic histology located in the cerebellum and/or fourth ventricle (PMID: 32239782)

* Cases generally show a classical histologic pattern: Small round blue cell tumor; Sheets of densely packed undifferentiated (embryonal) cells; Individual cells with scant cytoplasm, high nuclear-to-cytoplasmic ratio, and salt-and-pepper chromatin; Presence of mitoses, apoptotic bodies, and Homer Wright rosettes

* High degree of hemorrhage relative to other subtypes

* Rare examples with anaplastic histology have been described (PMIDs: 21267586; 31104222)

* Activated WNT pathway signaling - commonly visualized by immunohistochemical studies showing nuclear beta-catenin staining

* Majority positive for synaptophysin; INI-1 staining should be retained (positive)

* Molecular subtyping may be performed immunohistochemically using Filamin A, YAP1, GAB1 and beta-catenin (PMIDs: 32239782, 21267586)