Advanced molecular pathology for rare tumours: A national feasibility study and model for centralised medulloblastoma diagnostics

AIMS: Application of advanced molecular pathology in rare tumours is hindered by low sample numbers, access to specialised expertise/technologies and tissue/assay QC and rapid reporting requirements. We assessed the feasibility of co‐ordinated real‐time centralised pathology review (CPR), encompassing molecular diagnostics and contemporary genomics (RNA‐seq/DNA methylation‐array). METHODS: This nationwide trial in medulloblastoma (<80 UK diagnoses/year) introduced a national reference centre (NRC) and assessed its performance and reporting to World Health Organisation standards. Paired frozen/formalin‐fixed, paraffin‐embedded tumour material were co‐submitted from 135 patients (16 referral centres). RESULTS: Complete CPR diagnostics were successful for 88% (120/135). Inadequate sampling was the most common cause of failure; biomaterials were typically suitable for methylation‐array (129/135, 94%), but frozen tissues commonly fell below RNA‐seq QC requirements (53/135, 39%). Late reporting was most often due to delayed submission. CPR assigned or altered histological variant (vs local diagnosis) for 40/135 tumours (30%). Benchmarking/QC of specific biomarker assays impacted test results; fluorescent in‐situ hybridisation most accurately identified high‐risk MYC/MYCN amplification (20/135, 15%), while combined methods (CTNNB1/chr6 status, methylation‐array subgrouping) best defined favourable‐risk WNT tumours (14/135; 10%). Engagement of a specialist pathologist panel was essential for consensus assessment of histological variants and immunohistochemistry. Overall, CPR altered clinical risk‐status for 29% of patients. CONCLUSION: National real‐time CPR is feasible, delivering robust diagnostics to WHO criteria and assignment of clinical risk‐status, significantly altering clinical management. Recommendations and experience from our study are applicable to advanced molecular diagnostics systems, both local and centralised, across rare tumour types, enabling their application in biomarker‐driven routine diagnostics and clinical/research studies.