Medulloblastoma case series

Fukuoka et al. conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and treated with reduced-dose craniospinal irradiation.

Among the patients, 23 were classified as having a standard risk and 15 as high risk according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months (12.0-231.0). The median CSI dose was 18 Gy (15.0-24.0) in both groups, and 5 patients in the high-risk group received a CSI dose of 18.0 Gy. Molecular subgrouping revealed that the standard-risk cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the high-risk cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 9 of the 31 Group 3/4 cases were subclassified as subclass II, III, and V, which were known to have an association with poor prognosis according to the novel subtyping among the subgroups. Patients with poor prognostic subtype showed worse prognosis than that of others (5-year progression survival rate 90.4% vs. 22.2%; p < 0.0001). The result was replicated in the multivariate analysis (hazard ratio 12.77, 95% confidence interval for hazard ratio 2.38-99.21, p-value 0.0026 for progression-free survival, hazard ratio 5.02, 95% confidence interval for hazard ratio 1.03-29.11, p-value 0.044 for overall survival).

Although these findings require validation in a larger cohort, the present findings suggest that novel subtyping of Group 3/4 medulloblastoma may be a promising prognostic biomarker even among patients treated with lower-dose CSI than standard treatment ¹⁾

76 adult medulloblastoma patients (62% male), with a median age of 32 years at diagnosis (range: 18-66), and median follow-up of 7.7 years (range: 0.6-27). A subset of 58 patients had molecular subgroup characterization - 37 SHH-activated, 12 non-WNT/non-SHH, and 9 WNT-activated. 67% underwent gross total resection, 75% received chemotherapy at diagnosis, and 97% received craniospinal irradiation with boost. Median overall survival (OS) for the whole cohort was 14.8 years. The 2, 5, and 10-year OS was 93% (95% CI: 88-99%), 86% (78-94%), and 64% (53-78%), respectively. Survival was longer for younger patients (≥30 years old: 9.9 years; <30 years old: estimated >15.4 years; Log-rank p<0.001). There was no survival difference by molecular subgroup or extent of resection. Only age at diagnosis remained significant in multivariate survival analyses.

Neth et al. from the Mayo Clinic Rochester, report one of the largest retrospective cohorts in adult medulloblastoma patients with molecular subtyping. Survival and molecular subgroup frequencies were similar to prior reports. Survival was better for adult patients younger than 30 years at diagnosis and was not significantly different by molecular subgroup or management characteristics (extent of resection, RT characteristics, or chemotherapy timing or regimen) ²⁾.

25 patients were included, with a median age of 11.4 years; 8 had metastases. According to 2016-2021 WHO-classification, 14 had SHH subgroup tumors(six TP53 mutated,one + MYC,one + NMYC amplification), 11 non-WNT/non-SHH (two with MYC/MYCN amplification).Thirteen had received HART-CSI, 11 standard-CSI, one HFRT; all post-radiation chemotherapy(CT), 16 also pre-RT. Median time to relapse (local-LR in nine, distant-DR in 14, LR + DR in two) was 26 months. Fourteen patients were re-operated, in five cases excising single DR-sites, thereafter three received CT, two after re-RT; out of 11 patients not re-operated, four had re-RT as first treatment and seven after CT. Re-RT was administered at median 32 months after first RT: focally in 20 cases, craniospinal-CSI in five. Median post-relapse-PFS/after re-RT was 16.7/8.2 months, while overall survival-OS was 35.1/23.9 months, respectively. Metastatic status both at diagnosis/relapse negatively affected outcome and re-surgery was prognostically favorable. PD after re-RT was however significantly more frequent in SHH (with a suggestive association with TP53 mutation, p = 0.050). We did not observe any influence of biological subgroups on PFS from recurrence while SHH showed apparently worse OS compared to non-WNT/non-SHH group.

Conclusions: Re-surgery + reRT can prolong survival; a substantial fraction of patients with worse outcome belongs to the SHH-subgroup ³⁾.

An analysis of 118 patients of Medulloblastoma who underwent surgical treatment at National Institute of Mental Health and Neurosciences, Bangalore India, over a 7-year period (2005-2011) is presented. The clinical profile, radiologic characteristics, surgical nuances, and survival patterns are discussed. The relevant statistical analysis was done using SPSS software, version 22.0.

The mean age of the cohort was 12 years (12.3 ± 8.7). The primary manifestation was raised intracranial tension headache in 53 patients (44.9%), which was the predominant symptom in large cell/anaplastic (LCA)- and WNT-activated subgroups. The median preoperative Karnofsky performance score was 60 (60.6 ± 12.9). Vermian and hemispheric location of tumor was most commonly observed in non-WNT/non-SHH (groups 3 and 4; 91.7%) and SHH-activated (42.9%) subgroups, respectively. Ninety-two patients (78%) underwent preoperative ventriculoperitoneal shunts (VPS) for obstructive hydrocephalus (HCP) and 14 patients (11.8%) underwent VPS in the postoperative period. The median overall survival (OS) for the whole group was 82.1 ± 5.7 months and the median recurrence-free survival was 51.0 ± 4.8 months. While radiotherapy had a significant influence on OS, progression-free survival was influenced by radiotherapy as well as chemotherapy in both pediatric and adult cohort. Desmoplastic/nodular subtype and WNT-activated subgroup had the best prognosis; LCA and non-WNT/non-SHH had the worst prognosis.

The majority of the patients were pediatric in the study. Age, hemispheric location of the tumor, the extent of resection, and adjuvant therapy status were the important clinical prognostic factors for survival. Surgery for medulloblastoma (MB) is formidable, and ventriculoperitoneal shunts (VPS) can be considered in persistent symptomatic and progressive obstructive hydrocephalus. The study on pediatric and adult MB validates the prognostic significance of various clinical, radiologic, and histo-molecular parameters of MB ⁴⁾.

Ninety-five cases of Medulloblastoma (MB) with adequate tissue were included. Molecular subgrouping was performed by IHC for β-catenin, GAB1 and YAP1; FISH for MYC amplification, and sequencing for CTNNB1, and by NanoString Assay on the same set of MBs. A subset of cases was subjected to 850k DNA methylation array.

IHC + FISH classified MBs into 15.8% WNT, 16.8% SHH, and 67.4% non-WNT/non-SHH subgroups; with MYC amplification identified in 20.3% cases of non-WNT/non-SHH. NanoString successfully classified 91.6% MBs into 25.3% WNT, 17.2% SHH, 23% Group 3 and 34.5% Group 4. However, NanoString assay failure was seen in eight cases, all of which were > 8-years-old formalin-fixed paraffin-embedded tissue blocks. Concordant subgroup assignment was noted in 88.5% cases, while subgroup switching was seen in 11.5% cases. Both methods showed prognostic correlation. Methylation profiling performed on discordant cases revealed 1 out of 4 extra WNT identified by NanoString to be WNT, others aligned with IHC subgroups; extra SHH by NanoString turned out to be SHH by methylation.

Both IHC supplemented by FISH and NanoString are robust methods for molecular subgrouping, albeit with few disadvantages. IHC cannot differentiate between Groups 3 and 4, while NanoString cannot classify older-archived tumors, and is not available at most centres. Thus, both the methods complement each other and can be used in concert for high confidence allotment of molecular subgroups in clinical practice ⁵⁾.

Data were obtained from 82 patients with medulloblastoma at a single center, Beijing Tiantan Hospital. Based on medical records, we created two independent samples: the cerebellar mutism syndrome CMS group comprising 23 patients and the non-CMS group comprising 23 patients. Pre-operative imaging was studied by performing quantitative assessments of specific indicators.

The CMS group showed greater differences in pre-operative imaging data with the non-CMS group. The Aaxi/daxi ratio in pre-operative MR imaging captured in the axial plane was used to quantify the compression of the cerebellum and brainstem, and significant differences were observed between the CMS group and non-CMS group (p = 0.0002). In the sagittal plane, Dsag*dsag was used to quantify the area of the tumor that invaded the brainstem, and significant differences were observed between the two groups (p = 0.0003). In the coronal plane, Acor/dcor was used to quantify the compression of the upper functional brain region, and significant differences were noted between the two groups (p = 0.0219). Additionally, Evans' index was introduced to quantify the degree of hydrocephalus. The CMS group tended to show an increased Evans' index (p = 0.0027).

Based on pre-operative imaging data, some reproducible predictors, such as Aaxi/daxi, Dsag*dsag, Acor/dcor, and Evans' index, were established ⁶⁾.

A total of 67 pediatric cases of newly diagnosed medulloblastoma were included in a study. All of the children were treated at Xinhua Hospital between January 2007 and June 2013. The authors retrospectively analyzed the clinical data, treatment modalities, and outcome. The male-to-female ratio was 2:1, and the patients' median age at diagnosis was 51.96 months (range 3.96-168.24 months). The median duration of follow-up was 32 months (range 3-70 months).

At the most recent follow-up date, 31 patients (46%) were alive, 30 (45%) had died, and 6 (9%) had been lost to follow-up. The estimated 3-year overall survival and progression-free survival, based on Kaplan-Meier analysis, were 55.1% ± 6.4% and 45.6% ± 6.7%, respectively. Univariate analysis showed that standard-risk group (p = 0.009), postoperative radiotherapy (RT) combined with chemotherapy (p < 0.001), older age (≥ 3 years) at diagnosis (p = 0.010), gross-total resection (p = 0.012), annual family income higher than $3000 (p = 0.033), and living in urban areas (p = 0.008) were favorable prognostic factors. Multivariate analysis revealed that postoperative RT combined with chemotherapy was an independent prognostic factor (p < 0.001). The treatment abandonment rate in this cohort was 31% (21 of 67 cases).

There was a large gap between the outcome of medulloblastoma in Chinese children and the outcome in Western children. Based on this data, treatment abandonment was the major cause of therapeutic failure. Parents' misunderstanding of medulloblastoma played a major role in abandonment, followed by financial and transportation difficulties. Establishment of multidisciplinary treatment teams could improve the prognosis of medulloblastoma in Chinese children ⁷⁾.

Of 143 medulloblastoma patients, treated from 1991 to 2013, sufficient data were available for 130 patients (15 with Wnt, 30 with Shh, 30 with Group 3, and 55 with Group 4 medulloblastomas). Of these, 28 patients (22%) ultimately underwent CSF diversion surgery: 0% with Wnt, 29% with Shh, 29% with Group 3, and 43% with Group 4 tumors. Patients in the Wnt subgroup had a lower incidence of CSF diversion than all other patients combined (p = 0.04). Wnt patients had a lower Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) score (lower risk of CSF diversion, p = 0.045), were older, had smaller ventricles at diagnosis, and had no leptomeningeal metastases.

The overall rate of CSF diversion surgery for Shh, Group 3, and Group 4 medulloblastomas is around 30%, but no patients in the present series with a Wnt medulloblastoma required shunting. The low incidence of hydrocephalus in patients with Wnt medulloblastoma likely reflects both host factors (age) and disease factors (lack of metastases). The absence of hydrocephalus in patients with Wnt medulloblastomas likely contributes to their excellent rate of survival and may also contribute to a higher quality of life than for patients in other subgroups ⁸⁾.

Sure et al describe the incidence of secondary tumour manifestations in 66 patients of a single centre who underwent surgery for medulloblastoma between 1975 and 1990. No patient was excluded due to a poor postoperative course. Thirty-five patients showed evidence of secondary tumour growth. Of these, 17 suffered from local recurrence, and 27 developed metastastatic disease. The median latencies for secondary manifestations were 25 months for local recurrence (n = 17), 11 months for spinal metastases (n = 10), 15 months for supratentorial metastases (n = 8), 8 months for subleptomeningeal dissemination (n = 6), and 23 months for systemic metastases (n = 8). Two patients developed primary metastatic spread to the posterior fossa. Of 8 patients with supratentorial metastases, 6 developed fronto-basal lesions. In our patients, 89% of secondary lesions occurred within less than 3 years after primary diagnosis. 85% of patients with extra-axial tumour spread had been treated with a permanent shunt. Radical tumour resection and radiotherapy with 30 Gy to the neuraxis and 20 Gy boost to the posterior fossa was an important prognostic factor in this series. Patients with additional chemotherapy did not benefit significantly from this treatment. We conclude that optimal management of the primary lesions should aim at (i) total resection, (ii) avoid permanent shunting, and (iii) completion of the radiotherapy with inclusion of the medial frontobasal cisterns in the radiotherapeutic regimen. Our analysis suggests that adequate postoperative screening programmes should consist of 3-monthly scans of the neuraxis in the first three postoperative years and 6-monthly scans thereafter ⁹⁾.