When Standard Craniospinal Irradiation Leads to Severe Brainstem Toxicity: An M&M Case of Pineoblastoma in 22q11.2 Deletion Syndrome.

Abstract

Pineoblastoma is a rare WHO grade 4 embryonal tumor treated with maximal safe resection, craniospinal irradiation (CSI) with tumor-bed boost, and multi-agent chemotherapy. This report describes a 20-year-old woman with 22q11.2 deletion syndrome and localized pineoblastoma who developed severe, progressive brainstem radiation necrosis approximately nine months after guideline-concordant proton CSI to 36 Gy relative biological effectiveness (RBE) with sequential boost to 54 Gy RBE and concurrent vincristine. Despite contemporary proton planning and brainstem dose constraints, she developed refractory cerebellar and brainstem dysfunction. Biopsy confirmed treatment-related necrosis without recurrent tumor. The necrosis progressed despite dexamethasone, bevacizumab, and salvage laser interstitial thermal therapy (LITT). The patient's 22q11.2 deletion may have contributed to this exquisite radiosensitivity. Distal 22q11.2 loci encode ZNF280A, recently shown to promote homologous recombination (HR) repair of DNA double-strand breaks (DSBs), and its haploinsufficiency parallels established radiosensitivity syndromes. This case suggests patients with 22q11.2 deletion syndrome may have heightened susceptibility to radiation-induced normal tissue injury.