Molecular correlates of cerebellar mutism syndrome in medulloblastoma

Abstract

Background Cerebellar mutism syndrome (CMS) is a common complication following resection of posterior fossa tumors, most commonly after surgery for medulloblastoma. Medulloblastoma subgroups have historically been treated as a single entity when assessing CMS risk; however, recent studies highlighting their clinical heterogeneity suggest the need for subgroup-specific analysis. Here, we examine a large international multicenter cohort of molecularly characterized medulloblastoma patients to assess predictors of CMS. Methods We assembled a cohort of 370 molecularly characterized medulloblastoma subjects with available neuroimaging from 5 sites globally, including Great Ormond Street Hospital, Christian Medical College and Hospital, the Hospital for Sick Children, King Hussein Cancer Center, and Lucile Packard Children’s Hospital. Age at diagnosis, sex, tumor volume, and CMS development were assessed in addition to molecular subgroup. Results Overall, 23.8% of patients developed CMS. CMS patients were younger (mean difference −2.05 years ± 0.50, P = 0.0218) and had larger tumors (mean difference 10.25 cm3 ± 4.60, P = 0.0010) that were more often midline (odds ratio [OR] = 5.72, P < 0.0001). In a multivariable analysis adjusting for age, sex, midline location, and tumor volume, Wingless (adjusted OR = 4.91, P = 0.0063), Group 3 (adjusted OR = 5.56, P = 0.0022), and Group 4 (adjusted OR = 8.57 P = 9.1 × 10−5) tumors were found to be independently associated with higher risk of CMS compared with sonic hedgehog tumors. Conclusions Medulloblastoma subgroup is a very strong predictor of CMS development, independent of tumor volume and midline location. These findings have significant implications for management of both the tumor and CMS.

The Clinical and Prognostic Impact of the Choice of Surgical Approach to Fourth Ventricular Tumors in a Single-Center, Single-Surgeon Cohort of 92 Consecutive Pediatric Patients

“…According to our data, the development of CM after posterior fossa surgery in children appears to be a more complex phenomenon, requiring a combination of 1) surgery-unrelated factors (e.g., location of the tumor, medulloblastoma histology, brainstem infiltration) and 2) surgery-related factors (e.g., surgical manipulation near the dentate nuclei or the superior/middle cerebellar peduncles causing injury to the dento-rubro-thalamo-cortical pathways, inadequate use of self-retaining retractors and ultrasonic aspiration) ( 28 , 35 , 36 , 38 , 39 ). The risk factors identified in most papers ( 28 ) are mainly surgery unrelated: midline location (vermis and/or fourth ventricle), brainstem infiltration/compression, medulloblastoma histology with higher risk for 3–4 molecular subgroups ( 40 ), and tumor size ( 41 , 42 ).…”

Postoperative MRI features of cerebellar mutism syndrome: a retrospective cohort study

“…Other studies found a higher or lower proportion of males in the pCMS group than in the non-pCMS group, but the difference was not significant. 8,[22][23][24] Linguistic studies have found that males lag behind females in early language development and are more vulnerable to language deficits than females. [25][26][27] We presume that the cerebellum may play an indispensable role in early language learning, especially for the Chinese language.…”

Cerebellar mutism syndrome: From pathophysiology to rehabilitation

“…In recent years, four molecular subgroups of MB have been identified through transcriptional profile studies: sonic hedgehog [SHH], wingless [WNT], group 3, and group 4 (Ramaswamy and Taylor, 2017;Northcott et al, 2019). In this sense, it is interesting to note that several studies have recently identified the SHH subgroup as a significant factor in reducing the risk of post-operative CMS (Jabarkheel et al, 2020). The influence in the onset of post-operative CMS is probably the result of the cellular origin of a the subgroup rather than of the molecular characteristics: indeed, SHH medulloblastoma originates from the outer granular layer and therefore the tumor will typically develop within the cerebellar hemispheres; on the other hand, the origins from the lower rhombic lip, Nestin + cells, and unipolar brush cells, respectively of the WNT subgroups, 3 and 4 (Vladoiu et al, 2019), will give rise to tumors with an intimate relationship with the structures of the fourth ventricle, causing a greater risk of damage to the DRTT pathway during resection.…”