Evolving Biology and Therapy of WNT-Activated Medulloblastoma

WNT-activated medulloblastoma is one of the 4 molecularly defined subgroups of medulloblastoma and is characterized by distinct molecular, biological, and clinical features. These tumors originate from progenitor cells in the lower rhombic lip, leading to a characteristic anatomical location: midline, often involving the fourth ventricle and dorsal brainstem. This distinct location can help differentiate WNT-activated medulloblastomas from other subtypes on MRI. Although imaging may suggest WNT-activated medulloblastoma, a tissue diagnosis is required. WNT-activated medulloblastoma exhibits several unique histologic features that aid in diagnosis, and nearly all cases harbor either somatic CTNNB1 mutations or germline APC mutations. Treatment of all medulloblastoma is multimodal and includes maximal safe resection, radiotherapy, and adjuvant therapy. However, perhaps the most notable feature of WNT-activated medulloblastoma is the excellent prognosis associated with these tumors under current therapeutic regimens. The vasculature of WNT-activated medulloblastoma is thought to contribute to these favorable outcomes, as it mimics peripheral vascular endothelium, functionally eliminating the blood–brain barrier and increasing tumor susceptibility to systemic therapies. However, this vascular feature poses some challenges during surgical resection, as WNT-activated medulloblastomas carry an increased risk of intratumoral hemorrhage. With 5-year progression-free and overall survival exceeding 90% for WNT-activated medulloblastoma, and given the significant morbidity and late effects of current treatments, several trials are evaluating de-escalation of both craniospinal radiotherapy and adjuvant chemotherapy. Results of these trials are pending, but preliminary findings suggest that dose reductions can decrease long-term side effects while maintaining comparable progression-free and overall survival.