A 3-year-old child presents with signs of raised intracranial pressure and MRI shows a midline posterior fossa mass with gadolinium enhancement and drop metastases along the spinal cord. Histology shows small blue round cells with Homer Wright (neuroblastic) rosettes and MASH1/ATOH1 expression. Molecular testing shows WNT pathway activation (beta-catenin nuclear accumulation). Per WHO CNS5 2021, this tumor is classified as:

• A Ependymoma, posterior fossa group A (PFA) — worst prognosis ependymoma, EZHIP overexpression causing H3K27me3 loss
• B Medulloblastoma, WNT-activated — the best prognosis molecular subgroup, rarely metastatic at diagnosis; WNT activation via CTNNB1 mutation causes nuclear beta-catenin accumulation ✓
• C Medulloblastoma, SHH-activated, TP53-wildtype — favourable prognosis subgroup with PTCH1 and SMO mutations
• D AT/RT (atypical teratoid/rhabdoid tumor) — SMARCB1/INI1 loss on IHC is the diagnostic hallmark

Explanation

The 2021 WHO CNS5 classifies medulloblastoma into four molecular subgroups: WNT-activated, SHH-activated (TP53-wildtype and TP53-mutant), Group 3, and Group 4. WNT-activated medulloblastoma carries the best prognosis (5-year OS ~95%) and is characterized by activating mutations in CTNNB1 (beta-catenin) causing nuclear beta-catenin accumulation (demonstrable by IHC), monosomy 6, and is associated with CXCR6 and DKK2 as molecular markers. Despite the presence of drop metastases at diagnosis in this vignette, WNT-activated tumors still have excellent outcomes with standard therapy. PFA ependymoma shows H3K27me3 loss and EZHIP overexpression. SHH medulloblastoma involves hedgehog pathway mutations. AT/RT requires SMARCB1/SMARCA4 loss on IHC for diagnosis.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.