Recurrent medulloblastoma is a daunting therapeutic challenge as it is almost universally fatal. Recent studies confirmed that medulloblastoma comprises four distinct subgroups. We sought to delineate subgroup specific differences in medulloblastoma recurrence patterns.
We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children between 1994-2012, and performed molecular subgrouping on FFPE tissues using a nanoString-based assay. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence and survival post-recurrence were determined in a subgroup specific fashion. Subgroup specific recurrence patterns were confirmed in two independent, non-overlapping FFPE validation cohorts. Where possible molecular subgrouping was performed on tissue obtained from both the initial surgery and at recurrence.
A screening cohort of 30 recurrent medulloblastomas was assembled; nine with local recurrences, and 21 metastatic. When re-analysed in a subgroup specific manner, local recurrences were more frequent in SHH tumours (8/9, 88%) and metastatic recurrences were more common in Group 3 and 4 (17/20 [85%] with one WNT, p=0.0014, local vs metastatic recurrence, SHH vs Group 3 vs Group 4). The subgroup specific location of recurrence was confirmed in a multicenter validation cohort (p=0·0013 for local vs metastatic recurrence SHH vs Group 3 vs Group 4, n=77), and a second independent validation cohort comprising 96 recurrences (p<0·0001 for local vs metastatic recurrence SHH vs Group 3 vs Group 4, n=96). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival post recurrence was significantly longer in Group 4 patients (p=0·013) as confirmed in a multicenter validation cohort (p=0·0075). Strikingly, subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs.
Medulloblastoma does not switch subgroup at the time of recurrence further highlighting the stability of the four principle medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups were observed which have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of SHH patients. Refinement of therapy for Groups 3 and 4 should focus on the metastatic compartment, as it is the near universal cause of patient deaths.