MPC-02 REVIEW OF MEDULLOBLASTOMA FOR THE ASSESSMENT OF CONSENSUS IN PATHOLOGICAL DIAGNOSIS USING JPMNG CASES

Medulloblastoma (MB) is now classified by WHO 2016 classification as “genetically defined” and “histologically defined” variants. The aim of this study is to search for consensus on pathological diagnosis and assess the correlation between the central pathological diagnosis and the molecular subgrouping. We performed the pathological and molecular analyses in a total of 176 JPMNG (The Japan Pediatric Molecular Neuro-Oncology Group) cases. The diagnosis of MB was made by three expert neuropathologists (AS, JH, and TH) without knowledge of the molecular data. Subgroup affiliation was determined by expression profiling of 22 medulloblastoma subgroup-specific genes using the nanoString nCounter system. Histologically, classic MBL accounted for approximately 80% of all MB cases. Genetic analyses of 176 cases revealed four distinct molecular subgroups: WNT (14%), SHH (27%), group 3 (16%), and group 4 (43%). The central review reached a diagnosis of AT/RT for 3 cases that had been diagnosed as MB by the local pathologists. Immunohistochemically, WNT MBs showed nuclear accumulation of β-catenin protein, but the immunoreactivity was patchy in approximately one-quarter of WNT cases. GAB1 often exhibited little or no reactivity in the SHH subgroup. No reliable staining was observed for YAP1. All D/N MBL (16 cases) or MBEN (6 cases) were defined as SHH tumors. All MBEN cases were in infants (<3 years of age), and genetically subdivided into SHH-TP53 wild-type tumors. Variable degrees of anaplasia, including LC/A MB, occur across the genetic subgroups, and the LC/A MB WNT type was rare (2/24=8.3%) among WNT subgroups. This study demonstrated that the combination of morphological and molecular analyses can precisely diagnose MB. More robust, surrogate markers should be developed as ancillary diagnostic testing for subgroup classification. Further exploration of the clinical significance of the variable degree of LC/A histology and some subtypes (i.e. LC/A, WNT) will be necessary for risk stratification.